JP2014533662A - Nitrogen-containing fused cyclic compounds as CRTH2 receptor antagonists - Google Patents

Abstract

The present invention relates to a nitrogen-containing fused cyclic compound as a CRTH2 receptor antagonist represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof. Here, X1, X2, X3, X4, X5, W, X, Y, L1, L2, L3, A, and B are defined in the specification. The present invention further relates to a method for producing the compound, a drug formulation and a drug composition containing the compound; And the use of the stereoisomers thereof.

Description

  The present invention belongs to the pharmaceutical technical field, and a method for producing a nitrogen-containing fused cyclic compound as a CRTH2 receptor antagonist, a pharmaceutically acceptable salt thereof and a stereoisomer thereof; a drug formulation and a drug composition containing the compound And the use of said compounds, their pharmaceutically acceptable salts and their stereoisomers for the preparation of medicaments for the treatment and / or prevention of diseases related to CRTH2 activity.

  CRTH2 receptor is a G protein-coupled, chemo-inducible receptor that is expressed in Th2 cells and eosinophils. Th2 polarization was observed in allergic diseases such as asthma, allergic rhinitis, hereditary allergic dermatitis and allergic conjunctivitis. Th2 cells control allergic diseases through the production of Th2-type cytokines (eg IL-4, IL-5 and IL-3). In allergic diseases, these Th2-type cytokines directly or indirectly induce, for example, migration, activation, triggering and survival extension of responding cells such as eosinophils and basophils.

PGD ₂ (prostaglandin D ₂ ) is a ligand for CRTH2 and is produced from mast cells and other target cells in allergic diseases. In human cells, PGD ₂ induces migration and activation of Th2 cells, eosinophils and basophils via CRTH2. Therefore, antagonists that suppress the binding of CRTH2 and PGD ₂ are considered useful for the treatment of allergic diseases such as asthma, allergic rhinitis, hereditary allergic dermatitis and allergic conjunctivitis.

Numerous evidence has also shown that eosinophils are involved in sinusitis and Churg-Strauss syndrome. In these patient tissues, co-expression of mast cells and eosinophils was observed. This suggests that PGD ₂ produced from mast cells induces eosinophil assembly. Therefore, CRTH2 receptor antagonists are considered useful for the treatment of eosinophil-related diseases such as Churg-Strauss syndrome and sinusitis. Also, because CRTH2 receptor is expressed at high levels in basophils, CRTH2 receptor antagonists can treat CRTH2 receptor related diseases such as basophilic leukemia, chronic rubella and basophilia It is also useful.

  Ramatroban is marketed as an antagonist of thromboxane A2 receptor and has a strong platelet activating action, but its antagonistic action against CRTH2 receptor is weak and its selectivity is poor. Major side effects include purpura, PT / APTT prolongation, and subcutaneous bleeding.

  Currently, there is a shortage of effective CRTH2 receptor antagonists, so the development of compounds with new structures with high selectivity and high activity, optimized physicochemical properties, improved drug discovery, etc. is necessary.

  An object of the present invention is to provide a nitrogen-containing fused cyclic compound as a CRTH2 receptor antagonist.

Means for achieving such an object are as follows. That is,
A compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

ここで、X¹、X²、X³、X⁴それぞれ独立して、NまたはC(R¹)であり、X⁵はNまたはC(R²)であり；
R¹は水素、シアノ、ニトロ、ヒドロキシ、カルボキシ、アミノ、ハロゲン、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_3-8シクロアルキル、C_1-6アルコキシ、ハロゲン化C_1-6アルコキシ、C_3-8シクロアルキルC_1-6アルキル、C_2-6アルケニル、C_5-8シクロアルケニル、C_2-6アルキニル、C_1-6アルキルチオ、C_1-6アルキルアミノ、ジ(C_1-6アルキル)アミノ、C_1-6アルキルカルボニル、C_1-6アルキルカルバモイル、ホルムアミド基、C_1-6アルキルアミド基、C_1-6アルキルスルホニル、C_1-6アルキルアミノスルホニル、C_1-6アルキルスルホニルアミノ、ジ(C_1-6アルキル)カルバモイル、ジ(C_1-6アルキル)アミノスルホニル、C_1-6アルコキシカルボニルまたはC_1-6アルキルカルボニルオキシであり；
R²は水素、シアノ、ニトロ、ヒドロキシ、カルボキシ、アミノ、ハロゲン、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_3-8シクロアルキル、C_1-6アルコキシ、ハロゲン化C_1-6アルコキシ、C_3-8シクロアルキルC_1-6アルキル、C_2-6アルケニル、C_3-8シクロアルキルC_2-6アルケニル、C_5-8シクロアルケニル、C_5-8シクロアルケニルC_1-6アルキル、C_2-6アルキニル、C_1-6アルキルチオ、フェニル、フェニルC_1-6アルキル、ナフチル、C_3-8ヘテロシクロアルキル、C_3-8ヘテロシクロアルキルC_1-6アルキル、C_1-6アルキルアミノ、ジ(C_1-6アルキル)アミノ、C_1-6アルキルカルボニル、C_1-6アルキルカルバモイル、ホルムアミド基、C_1-6アルキルアミド基、C_1-6アルキルスルホニル、C_1-6アルキルアミノスルホニル、C_1-6アルキルスルホニルアミノ、ジ(C_1-6アルキル)カルバモイル、ジ(C_1-6アルキル)アミノスルホニル、C_1-6アルコキシカルボニルまたはC_1-6アルキルカルボニルオキシであり；

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L¹は-(C(R^1aR^1b))_p-であり、pは1、2、3、4、5または6であり；

が−C＝である場合、R^1aとR^1bはそれぞれ独立して、水素、ハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、ハロゲン化C_1-6アルコキシまたはC_3-8シクロアルキルであり；ここで、R^1aとR^1bがそれらに結合しているC原子と、C_3-8シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-8ヘテロシクロアルキルを形成しても良い；上記のC_3-8シクロアルキル及びC_3-8ヘテロシクロアルキルは任意に1、2、3、4、5、または6個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシまたはハロゲン化C_1-6アルコキシから選ばれ；

が−N−である場合、R^1aとR^1bはそれぞれ独立して水素、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-8シクロアルキルであり；ここで、R^1aとR^1bがそれらに結合しているC原子と、C_3-8シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-8ヘテロシクロアルキルを形成しても良い；上記のC_3-8シクロアルキル及びC_3-8ヘテロシクロアルキルは任意に1、2、3、4、5または6個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシまたはハロゲン化C_1-6アルコキシから選ばれ；
WはR^2aOC(O)-、(R^2a)₂NC(O)-、R^2aC(O)NHC(O)-、テトラゾリルまたはR^2aS(O)₂NHC(O)-であり；
R^2aは水素、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_3-8シクロアルキル、C_3-8ヘテロシクロアルキル、フェニルまたはトリルであり；
L²は-(C(R^3aR^3b))_p-であり、pは1、2、3、4、5または6であり；

が−C＝である場合、R^3aとR^3bはそれぞれ独立して水素、ハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-8シクロアルキルであり；ここで、R^3aとR^3bがそれらに結合しているC原子と、C_3-8シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-8ヘテロシクロアルキルを形成しても良い；上記のC_3-8シクロアルキル及びC_3-8ヘテロシクロアルキルは任意に1、2、3、4、5または6個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、ハロゲン化C_1-6アルコキシまたはC_3-8シクロアルキルから選ばれ；

が−N−である場合、R^3aとR^3bはそれぞれ独立して水素、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-8シクロアルキルであり；ここで、R^3aとR^3bがそれらに結合しているC原子と、C_3-8シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-8ヘテロシクロアルキルを形成しても良い；上記のC_3-8シクロアルキル及びC_3-8ヘテロシクロアルキルは任意に1、2、3、4、5または6個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、ハロゲン化C_1-6アルコキシまたはC_3-8シクロアルキルから選ばれ；
Xはアリール基またはヘテロ環基であり、Xは任意に1、2、3、4、5または6個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、ハロゲン化C_1-6アルコキシまたはC_3-8シクロアルキルから選ばれ；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはC_1-6アルキルであり；
YはC_3-8シクロアルキル、アリール基または3-10員ヘテロ環基であり、Yは任意に1、2、3、4、5または6個の置換基に置換されても良い；ここの置換基は、独立してヒドロキシ、ハロゲン、シアノ、ニトロ、C_1-6アルキル、ヒドロキシC_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、C_1-6アルコキシC_1-6アルキル、C_1-6アルコキシC_1-6アルコキシ、ハロゲン化C_1-6アルコキシ、C_3-8シクロアルキル、C_1-6アルキルアミノ、ジ(C_1-6アルキル)アミノ、C_1-6アルキルチオ、フェニル、フェノキシ、C_5-8ヘテロシクロアルキル、C_5-8ヘテロシクロアルコキシ、C_1-6アルキルカルボニル、C_1-6アルキルカルバモイル、ホルムアミド基、C_1-6アルキルアミド基、C_1-6アルキルスルホニル、C_1-6アルキルアミノスルホニル、C_1-6アルキルスルホニルアミノ、ジ(C_1-6アルキル)カルバモイル、ジ(C_1-6アルキル)アミノスルホニル、C_1-6アルコキシカルボニルまたはC_1-6アルキルカルボニルオキシから選ばれる。

Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ) and X ⁵ is N or C (R ² );
R ¹ is hydrogen, cyano, nitro, hydroxy, carboxy, amino, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 Alkoxy, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _5-8 cycloalkenyl, C _2-6 alkynyl, C _1-6 alkylthio, C _1-6 alkylamino, di (C _{1 -6} alkyl) amino, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylsulfonyl, C _1-6 alkylaminosulfonyl, C _1-6 Alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl, di (C _1-6 alkyl) aminosulfonyl, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy;
R ² is hydrogen, cyano, nitro, hydroxy, carboxy, amino, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 Alkoxy, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl C _2-6 alkenyl, C _5-8 cycloalkenyl, C _5-8 cycloalkenyl C _1-6 alkyl , C _2-6 alkynyl, C _1-6 alkylthio, phenyl, phenyl C _1-6 alkyl, naphthyl, C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl C _1-6 alkyl, C _1-6 alkyl Amino, di (C _1-6 alkyl) amino, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylsulfonyl, C _1-6 alkylamino sulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) Karubamo Le, di (C _1-6 alkyl) aminosulfonyl, be a C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , and p is 1, 2, 3, 4, 5 or 6;

Is —C═, R ^1a and R ^1b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _{1- 6} alkoxy or C _3-8 cycloalkyl; where R ^1a and R ^1b are attached to them and at least one of C _3-8 cycloalkyl or O, N or S atoms C _3-8 heterocycloalkyl may be formed; the above C _3-8 cycloalkyl and C _3-8 heterocycloalkyl are optionally substituted by 1, 2, 3, 4, 5, or 6 The substituents here are independently selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy That;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or C _3-8 cycloalkyl; where R ^1a and R ^1b are ^1b may form a C _3-8 cycloalkyl or C _3-8 heterocycloalkyl containing at least one of the O, N or S atoms with the C atom bonded to them; _3-8 cycloalkyl and C _3-8 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;
W is R ^2a OC (O)-, (R ^2a ) ₂ NC (O)-, R ^2a C (O) NHC (O)-, tetrazolyl or R ^2a S (O) ₂ NHC (O)-;
R ^2a is hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, phenyl or tolyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1, 2, 3, 4, 5 or 6;

Is —C═, R ^3a and R ^3b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-8 cycloalkyl; R ^3a and R ^3b may form a C atom bonded to them and a C _3-8 cycloalkyl or C _3-8 heterocycloalkyl containing at least one of O, N or S atoms. The above C _3-8 cycloalkyl and C _3-8 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently Selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy or C _3-8 cycloalkyl;

R ^3a and R ^3b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-8 cycloalkyl; wherein R ^3a and R ^3b are ^3b may form a C _3-8 cycloalkyl or C _3-8 heterocycloalkyl containing at least one of the O, N or S atoms with the C atom bonded to them; _3-8 cycloalkyl and C _3-8 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy or C _3-8 cycloalkyl;
X is an aryl group or a heterocyclic group, and X may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy, Selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy or C _3-8 cycloalkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-6 alkyl;
Y is C _3-8 cycloalkyl, an aryl group or a 3-10 membered heterocyclic group, Y may optionally be substituted with 1, 2, 3, 4, 5 or 6 substituents; Substituents are independently hydroxy, halogen, cyano, nitro, C _1-6 alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _{1- 6} alkyl, C _1-6 alkoxy C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _3-8 cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 Alkylthio, phenyl, phenoxy, C _5-8 heterocycloalkyl, C _5-8 heterocycloalkoxy, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _{1- 6} alkylsulfonyl, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 Cyl) carbamoyl, di (C _1-6 alkyl) aminosulfonyl, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy.

Preferred forms of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof are as follows.

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L¹は-(C(R^1aR^1b))_p-であり、pは1、2、3、4または5であり；

が−C＝である場合、R^1aとR^1bはそれぞれ独立して水素、ハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシまたはC_3-6シクロアルキルであり；ここで、R^1aとR^1bがそれらに結合しているC原子と、C_3-6シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-6ヘテロシクロアルキルを形成しても良い；上記のC_3-6シクロアルキル及びC_3-6ヘテロシクロアルキルは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_1-6アルコキシから選ばれ；

が−N−である場合、R^1aとR^1bはそれぞれ独立して水素、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-6シクロアルキルであり；ここで、R^1aとR^1bがそれらに結合しているC原子と、C_3-6シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-6ヘテロシクロアルキルを形成しても良い；上記のC_3-6シクロアルキル及びC_3-6ヘテロシクロアルキルは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシまたはハロゲン化C_1-6アルコキシから選ばれ；
WはR^2aOC(O)-、(R^2a)₂NC(O)-またはテトラゾリルであり、
R^2aは水素、C_1-6アルキルまたはC_3-8シクロアルキルであり；
L²は-(C(R^3aR^3b))_p-であり、pは1、2、3、4または5であり；

が−C＝である場合、R^3aとR^3bはそれぞれ独立して水素、ハロゲン、ヒドロキシ、C_1-6アルキルまたはC_3-6シクロアルキルであり；ここで、R^3aとR^3bがそれらに結合しているC原子と、C_3-6シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-6ヘテロシクロアルキルを形成しても良い；上記のC_3-6シクロアルキル及びC_3-6ヘテロシクロアルキルは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシまたはC_3-8シクロアルキルから選ばれ；

が−N−である場合、R^3aとR^3bはそれぞれ独立して水素、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-6シクロアルキルであり；ここで、R^3aとR^3bがそれらに結合しているC原子と、C_3-8シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC_3-6ヘテロシクロアルキルを形成しても良い；上記のC_3-6シクロアルキル及びC_3-6ヘテロシクロアルキルは任意に1、2、3、4、5または6個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、C_3-8シクロアルキルから選ばれ；
Xはアリール基またはヘテロ環基であり、Xは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシまたはC_3-8シクロアルキルから選ばれ；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはC_1-6アルキルであり；
YはC_3-8シクロアルキル、アリール基または3-10員ヘテロ環基であり、Yは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してヒドロキシ、ハロゲン、シアノ、C_1-6アルキル、ヒドロキシC_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、C_1-6アルコキシC_1-6アルキル、ハロゲン化C_1-6アルコキシ、C_3-8シクロアルキル、C_1-6アルキルアミノ、ジ(C_1-6アルキル)アミノ、C_1-6アルキルチオ、フェニル、フェノキシ、C_5-8ヘテロシクロアルキル、C_5-8ヘテロシクロアルコキシ、C_1-6アルキルカルボニル、C_1-6アルキルカルバモイル、ホルムアミド基、C_1-6アルキルアミド基、C_1-6アルキルアミノスルホニル、C_1-6アルキルスルホニルアミノ、ジ(C_1-6アルキル)カルバモイルまたはジ(C_1-6アルキル)アミノスルホニルから選ばれる。 Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ) and X ⁵ is N or C (R ² );
R ¹ is hydrogen, cyano, hydroxy, amino, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _{3 -8} cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _5-8 cycloalkenyl, C _1-6 alkylthio, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 Alkylcarbamoyl, formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl, di (C _1-6 alkyl) aminosulfonyl C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy;
R ² is hydrogen, cyano, amino, nitro, hydroxy, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl C _2-6 alkenyl, C _5-8 cycloalkenyl, C _5-8 cycloalkenyl C _1-6 alkyl, C _2-6 alkynyl, phenyl, phenyl C _1-6 alkyl, naphthyl, C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl C _1-6 alkyl, C _1-6 alkylamino, di (C _1-6 Alkyl) amino, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl or di ( C _1-6 alkyl) aminosulfonyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1, 2, 3, 4 or 5;

Is —C═, R ^1a and R ^1b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl. Where R ^1a and R ^1b are bound to the C atom and C _3-6 cycloalkyl or C _3-6 heterocycloalkyl containing at least one of O, N or S atoms The above C _3-6 cycloalkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; Are independently selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 alkoxy;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl; where R ^1a and R ^1b are ^1b may form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl containing at least one of O, N or S atoms with the C atom bonded to them; _3-6 cycloalkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C Selected from _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;
W is R ^2a OC (O)-, (R ^2a ) ₂ NC (O)-or tetrazolyl,
R ^2a is hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1, 2, 3, 4 or 5;

Is —C═, R ^3a and R ^3b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl or C _3-6 cycloalkyl; where R ^3a and R ^3b are a C atom bonded to have, C _3-6 cycloalkyl or O, may also form a C _3-6 heterocycloalkyl containing at least one of N or S atoms; above C _3-6 cycloalkyl Alkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C _1-6 alkyl , Halogenated C _1-6 alkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;

R ^3a and R ^3b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or C _3-6 cycloalkyl; where R ^3a and R ^3b are ^3b may form a C _3-8 cycloalkyl or C _3-6 heterocycloalkyl containing at least one of O, N or S atoms with the C atom bonded to them; _3-6 cycloalkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl;
X is an aryl group or a heterocyclic group, and X may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C ₁ Selected from _-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-6 alkyl;
Y is C _3-8 cycloalkyl, an aryl group or a 3-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2, 3, 4 or 5 substituents; Is independently hydroxy, halogen, cyano, C _1-6 alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, halogen C _1-6 alkoxy, C _3-8 cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylthio, phenyl, phenoxy, C _5-8 heterocycloalkyl, C _5-8 heterocycloalkoxy, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di ( C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) selected from aminosulfonyl That.

  Preferred forms of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof are as follows.

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に−N−であることはない；
L¹は-(C(R^1aR^1b))_p-であり、pは1、2、3または4であり；

である場合、R^1aとR^1bはそれぞれ独立して水素、ハロゲン、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-6シクロアルキルであり；ここで、R^1aとR^1bがそれらに結合しているC原子と、C_3-6シクロアルキルを形成しても良い；上記のC_3-6シクロアルキルは任意に1、2、3または4個の置換基に置換されても良い；ここの置換基は、ハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_1-6アルコキシから選ばれ；

である場合、R^1aとR^1bはそれぞれ独立して水素、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-6シクロアルキルであり；ここで、R^1aとR^1bがそれらに結合しているC原子と、C_3-6シクロアルキルを形成しても良い；上記のC_3-6シクロアルキルは任意に1、2、3または4個の置換基に置換されても良い；ここの置換基は、ハロゲン、ヒドロキシ、C_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシまたはハロゲン化C_1-6アルコキシから選ばれ；
WはR^2aOC(O)-または(R^2a)₂NC(O)-であり、
R^2aは水素、C_1-6アルキルまたはC_3-8シクロアルキルであり；
L²は-(C(R^3aR^3b))_p-であり、pは1、2、3または4であり；

である場合、R^3aとR^3bはそれぞれ独立して水素、ハロゲン、C_1-6アルキルまたはC_3-6シクロアルキルであり；

である場合、R^3aとR^3bはそれぞれ独立して水素、C_1-6アルキルまたはC_3-6シクロアルキルであり；
Xは6-10員アリール基または5-6員ヘテロ環基であり、Xは任意に1、2、3または4個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C_1-6アルキルまたはハロゲン化C_1-6アルキルから選ばれ；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはC_1-6アルキルであり；
YはC_3-8シクロアルキル、6-10員アリール基または5-10員ヘテロ環基であり、Yは任意に1、2、3または4個の置換基に置換されても良い；ここの置換基は、シアノ、ヒドロキシ、ハロゲン、C_1-6アルキル、ヒドロキシC_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、C_1-6アルコキシC_1-6アルキル、C_3-8シクロアルキル、C_1-6アルキルアミノ、ジ(C_1-6アルキル)アミノ、C_1-6アルキルチオ、C_5-8ヘテロシクロアルキル、C_5-8ヘテロシクロアルコキシ、C_1-6アルキルカルバモイル、ホルムアミド基、C_1-6アルキルアミド基、C_1-6アルキルアミノスルホニル、C_1-6アルキルスルホニルアミノ、ジ(C_1-6アルキル)カルバモイルまたはジ(C_1-6アルキル)アミノスルホニルから選ばれる。 Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 Alkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkyl Sulfonylamino, di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl;
R ² is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _5-8 cycloalkenyl C _1-6 alkyl, phenyl, phenyl C _1-6 alkyl, naphthyl, C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl C _1-6 alkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino Di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl;

Are each independently -N- or -C =, and

Are not simultaneously -N-;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1, 2, 3 or 4;

R ^1a and R ^1b are each independently hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl; where R ^1a and R ^1b are and C atoms to which they are attached, may also form a C _3-6 cycloalkyl; be C _3-6 cycloalkyl described above are substituted 1, 2, 3 or 4 substituents optionally Good; the substituents here are selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 alkoxy;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl; wherein R ^1a and R ^1b are C _3-6 cycloalkyl may form with the C atom attached; the above C _3-6 cycloalkyl may optionally be substituted with 1, 2, 3 or 4 substituents; The substituents here are selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;
W is R ^2a OC (O)-or (R ^2a ) ₂ NC (O)-
R ^2a is hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , and p is 1, 2, 3 or 4;

R ^3a and R ^3b are each independently hydrogen, halogen, C _1-6 alkyl or C _3-6 cycloalkyl;

R ^3a and R ^3b are each independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl;
X is a 6-10 membered aryl group or a 5-6 membered heterocyclic group, and X may be optionally substituted with 1, 2, 3 or 4 substituents; these substituents are independently Selected from halogen, hydroxy, C _1-6 alkyl or halogenated C _1-6 alkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-6 alkyl;
Y is C _3-8 cycloalkyl, a 6-10 membered aryl group or a 5-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2, 3 or 4 substituents; Substituents are cyano, hydroxy, halogen, C _1-6 alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _{3 -8} cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _5-8 heterocycloalkyl, C _5-8 heterocycloalkoxy, C _1-6 alkylcarbamoyl , Formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl It is.

  Preferred forms of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof are as follows.

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L¹は-(C(R^1aR^1b))_p-であり、pは1、2または3であり；

が−C＝である場合、R^1aとR^1bはそれぞれ独立して水素、ハロゲン、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-6シクロアルキルであり；

である場合、R^1aとR^1bはそれぞれ独立して水素、C_1-6アルキル、ハロゲン化C_1-6アルキルまたはC_3-6シクロアルキルであり；
WはR^2aOC(O)-であり、R^2aは水素またはC_1-4アルキルであり；
L²は-(C(R^3aR^3b))_p-であり、pは1、2または3であり；

である場合、R^3aとR^3bはそれぞれ独立して水素、ハロゲンまたはC_1-4アルキルであり；

である場合、R^3aとR^3bはそれぞれ独立して水素またはC_1-4アルキルであり；
Xは6-10員アリール基または5-6員ヘテロ環基であり、Xは任意に1、2または3個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、C_1-4アルキルまたはハロゲン化C_1-4アルキルから選ばれ；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはC_1-4アルキルであり；
Yは6-10員アリール基または5-10員ヘテロ環基であり、Yは任意に1、2または3個置換基に置換されても良い；ここの置換基は、ハロゲン、シアノ、C_1-6アルキル、ヒドロキシC_1-6アルキル、ハロゲン化C_1-6アルキル、C_1-6アルコキシ、C_1-6アルコキシC_1-6アルキル、C_3-8シクロアルキル、C_1-6アルキルアミノまたはジ(C_1-6アルキル)アミノから選ばれる。 Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ) and X ⁵ is N or C (R ² );
R ¹ is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino , C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl;
R ² is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 Alkenyl, C _5-8 cycloalkenyl C _1-6 alkyl, phenyl, C _1-6 alkylamino or di (C _1-6 alkyl) amino;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1, 2 or 3;

When R is -C =, R ^1a and R ^1b are each independently hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl;
W is R ^2a OC (O) —, R ^2a is hydrogen or C _1-4 alkyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1, 2 or 3;

R ^3a and R ^3b are each independently hydrogen, halogen or C _1-4 alkyl;

R ^3a and R ^3b are each independently hydrogen or C _1-4 alkyl;
X is a 6-10 membered aryl group or a 5-6 membered heterocyclic group, and X may be optionally substituted with 1, 2 or 3 substituents; these substituents are independently halogen, Selected from C _1-4 alkyl or halogenated C _1-4 alkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-4 alkyl;
Y is a 6-10 membered aryl group or a 5-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2 or 3 substituents; the substituents here are halogen, cyano, C _{1 -6} alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkylamino or Selected from di (C _1-6 alkyl) amino.

  Preferred forms of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof are as follows.

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に−N−であることはない；
L¹は-(C(R^1aR^1b))_p-であり、pは1または2であり、

である場合、R^1aとR^1bはそれぞれ独立して水素、ハロゲンまたはC_1-4アルキルであり；

である場合、R^1aとR^1bはそれぞれ独立して水素またはC_1-4アルキルであり；
Wは-C(O)OHであり；
L²は-(C(R^3aR^3b))_p-であり、pは1または2であり、
R^3aとR^3bはそれぞれ独立して水素またはC_1-4アルキルであり；
Xはフェニル、ピリジルまたはピラジニルであり、Xは任意に1または2個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、C_1-4アルキルまたはハロゲン化C_1-4アルキルから選ばれ；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはC_1-4アルキルであり；
Yは6-10員アリール基または5-10員ヘテロ環基であり、Yは任意に1、2または3個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、シアノ、C_1-4アルキルまたはハロゲン化C_1-4アルキルから選ばれる。 Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ) and X ⁵ is N or C (R ² );
R ¹ is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, formamide group, C _1-4 alkylamide group or C _3-6 cyclo Is alkyl;
R ² is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or phenyl;

Are each independently -N- or -C =, and

Are not simultaneously -N-;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1 or 2,

R ^1a and R ^1b are each independently hydrogen, halogen or C _1-4 alkyl;

R ^1a and R ^1b are each independently hydrogen or C _1-4 alkyl;
W is -C (O) OH;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1 or 2,
R ^3a and R ^3b are each independently hydrogen or C _1-4 alkyl;
X is phenyl, pyridyl or pyrazinyl, X may optionally be substituted with 1 or 2 substituents; these substituents are independently halogen, C _1-4 alkyl or halogenated C _1- Selected from ₄ alkyls;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-4 alkyl;
Y is a 6-10 membered aryl group or a 5-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2 or 3 substituents; the substituents are independently halogen, Selected from cyano, C _1-4 alkyl or halogenated C _1-4 alkyl.

  Preferred forms of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof are as follows.

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L¹は-(C(R^1aR^1b))_p-であり、pは1または2であり、R^1aとR^1bはそれぞれ独立して水素であり；
Wは-C(O)OHであり；
L²は- CH₂-であり；
Xはフェニル、ピリジルまたはピラジニルであり、Xは1また2個の置換基に置換されても良い；ここの置換基は、独立してフッ素、塩素、メチル、エチル、イソプロピルまたはトリフルオロメチルから選ばれ；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはメチルであり；
Yはフェニル、ピリジル、ピラゾリル、ナフチルまたは2,3-ジヒドロベンゾ[b][1,4]ジオキサニルであり、Yは任意に1、2または3個の置換基に置換されても良い；ここの置換基は、独立してフッ素、塩素、臭素、シアノ、メチル、エチル、イソプロピル、tert-ブチルまたはトリフルオロメチルから選ばれる。 Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ) and X ⁵ is N or C (R ² );
R ¹ is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, methylamino, formamide group, acetylamino or C _3-6 cycloalkyl;
R ² is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or phenyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1 or 2, and R ^1a and R ^1b are each independently hydrogen;
W is -C (O) OH;
L ² is —CH ₂ —;
X is phenyl, pyridyl or pyrazinyl, X may be substituted by 1 or 2 substituents; these substituents are independently selected from fluorine, chlorine, methyl, ethyl, isopropyl or trifluoromethyl That;
L ³ is —N (R ^5a ) —C (O) — and R ^5a is hydrogen or methyl;
Y is phenyl, pyridyl, pyrazolyl, naphthyl or 2,3-dihydrobenzo [b] [1,4] dioxanyl, Y may optionally be substituted with 1, 2 or 3 substituents; The substituents are independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl.

  Preferred forms of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof are as follows.

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L¹は-CH₂-であり；
Wは-C(O)OHであり；
L²は-CH₂-であり；
Xはフェニル、ピリジルまたはピラジニルであり、Xは任意に1または2個の置換基に置換されても良い；ここの置換基は、それぞれ独立して、フッ素、塩素、メチル、エチルまたはトリフルオロメチルから選ばれ；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはメチルであり；
Yはフェニル、ピリジル、ピラゾリル、ナフチルまたは2,3-ジヒドロベンゾ[b][1,4]ジオキサニルであり、Yは任意に1、2または3個の置換基に置換されても良い；ここの置換基は、独立してフッ素、塩素、臭素、シアノ、メチル、エチル、イソプロピル、tert-ブチルまたはトリフルオロメチルから選ばれる。 Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ) and X ⁵ is N or C (R ² );
R ¹ is hydrogen, fluorine, chlorine or C _1-4 alkyl;
R ² is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ¹ is —CH ₂ —;
W is -C (O) OH;
L ² is —CH ₂ —;
X is phenyl, pyridyl or pyrazinyl, and X may optionally be substituted with 1 or 2 substituents; each substituent is independently fluorine, chlorine, methyl, ethyl or trifluoromethyl Chosen from;
L ³ is —N (R ^5a ) —C (O) — and R ^5a is hydrogen or methyl;
Y is phenyl, pyridyl, pyrazolyl, naphthyl or 2,3-dihydrobenzo [b] [1,4] dioxanyl, Y may optionally be substituted with 1, 2 or 3 substituents; The substituents are independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl.

  Preferred forms of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof are as follows.

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L¹は-CH₂-であり；
Wは-C(O)OHであり；
L²は-CH₂-であり；
Xはフェニル、ピリジルまたはピラジニルであり；
L³は-N(R^5a)-C(O)-であり、R^5aは水素またはメチルであり；
Yはフェニル、ピリジル、ピラゾリル、ナフチルまたは2,3-ジヒドロベンゾ[b][1,4]ジオキサニルであり、Yは任意に1または2個の置換基に置換されても良い；ここの置換基は、独立してフッ素、塩素、臭素、シアノ、メチル、エチル、イソプロピル、tert-ブチルまたはトリフルオロメチルから選ばれる。 Where X ¹ , X ² , X ³ and X ⁴ are each independently C (R ¹ ), X ⁴ is N or C (R ¹ ), and X ⁵ is N or C (R ² ). Is;
R ¹ is hydrogen or fluorine;
R ² is hydrogen or C _1-4 alkyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ¹ is —CH ₂ —;
W is -C (O) OH;
L ² is —CH ₂ —;
X is phenyl, pyridyl or pyrazinyl;
L ³ is —N (R ^5a ) —C (O) — and R ^5a is hydrogen or methyl;
Y is phenyl, pyridyl, pyrazolyl, naphthyl or 2,3-dihydrobenzo [b] [1,4] dioxanyl, Y may optionally be substituted with 1 or 2 substituents; Are independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl.

  Preferred forms of the compound represented by the general formula (I), pharmaceutically acceptable salts and stereoisomers thereof include the following partial compounds.

In the present specification, “halogen” means fluorine, chlorine, bromine or iodine.
As used herein, “C _1-6 alkyl” means a linear or branched alkyl having 1 to 6 C atoms. For example, “C _1-4 alkyl”, “C _1-3 alkyl”, “C _2-4 alkyl”, “C _2-5 alkyl” and the like are included. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl and the like, but are not limited thereto. “C _1-4 alkyl” in the present specification is an example containing 1 to 4 C atoms mentioned in the above examples.

In the present specification, “C _2-6 alkenyl” means a straight or branched alkenyl having a double bond and having 2 to 6 C atoms. For example, “C _2-4 alkenyl”, “C _2-5 alkenyl”, “C _2-3 alkenyl” and the like are included. Examples thereof are vinyl group, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1- Methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl- 1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3- Butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl -1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3 -Pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl -3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl Ru-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl- Examples thereof include, but are not limited to, 2-propenyl, 1,3-butadiene group, 1,3-pentadiene group, 1,4-pentadiene group, 1,4-hexadiene group and the like.

As used herein, “C _5-8 cycloalkenyl” means a cyclic functional group containing 5 to 8 C atoms and containing a double bond. For example, “C _5-6 cycloalkenyl”, “C _5-7 cycloalkenyl” and the like are included. Examples thereof include cyclopentenyl, 1,3-cyclopentadiene group, cyclohexenyl, 1,3-cyclohexadiene group, 1,4-cycloheptadiene group, cycloheptenyl, 1,3-cycloheptadiene group, 1,3, Examples thereof include, but are not limited to, a 5-cycloheptatriene group, a cyclooctenyl group, a 1,3,5-cyclooctatriene group, and the like.

As used herein, “C _2-6 alkynyl” means straight or branched alkynyl having a triple bond and having 2 to 6 C atoms. For example, “C _2-5 alkynyl”, “C _2-4 alkynyl”, “C _2-3 alkynyl” and the like are included. Examples include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl- 3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl- 2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2- Pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, Examples thereof include, but are not limited to, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.

In the present specification, “C _1-6 alkoxy” is a substituent bonded in the form of “C _1-6 alkyl-O—”, and “C _1-6 alkyl” is as defined above; For example, “C _1-4 alkoxy”, “C _1-3 alkoxy”, “C _2-4 alkoxy”, “C _2-5 alkoxy” and the like are included.

As used herein, “C _1-6 alkylthio” is a substituent bonded in the form of “C _1-6 alkyl-S—”, and “C _1-6 alkyl” is as defined above; For example, “C _1-4 alkylthio”, “C _1-3 alkylthio”, “C _2-4 alkylthio”, “C _2-5 alkylthio” and the like are included.

The “C _3-8 cycloalkyl” in the present specification means a cycloalkyl having 3 to 8 C atoms. For example, “C _3-6 cycloalkyl”, “C _4-6 cycloalkyl”, “C _5-6 cycloalkyl” and the like are included. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

"Halogenated C _1-6 alkyl" in the present specification, the term "halogenated C _1-6 alkoxy", as defined in the preceding "C _1-6 alkyl", "C _1-6 alkoxy" is one or Substituents substituted by a plurality of “halogens”, preferably chlorine or fluorine substitution.

As used herein, “C _3-8 heterocycloalkyl” refers to a substituent formed by substituting one or more C atoms in C _3-8 cycloalkyl with S, O, N, or C (O). And “C _3-8 cycloalkyl” is as defined above.

The “aryl group” in the present specification means a 6- to 14-membered cyclic aromatic group in which all atoms constituting the ring are C atoms. 6-8 membered monocyclic aryl groups and 8-14 membered fused ring aryl groups are included. A 6-8 membered monocyclic aryl group is an aryl group which is unsaturated as a whole, and includes, for example, phenyl, cyclooctatetraenyl and the like. The 8- to 14-membered fused ring aryl group is a fused ring aryl group in which at least one ring is an unsaturated aromatic ring formed by sharing two or more adjacent C atoms. For example, unsaturated 8-14 membered fused aryl groups such as naphthyl, phenanthryl and the like. Also included are partially saturated fused ring aryl groups such as benzo C _3-8 cycloalkyl, benzo C _4-8 cycloalkenyl. Specific examples thereof include 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like. The “6-10 membered aryl group” means a 6-10 membered cyclic aromatic group in which all ring atoms are C atoms. Monocyclic aryl groups and fused ring aryls are included, and the fused ring aryl groups may be unsaturated or partially saturated.

  The “heterocyclic group” in the present specification means a cyclic group having 3 to 14 atoms constituting the ring and at least one of these atoms being a heteroatom. For example, “3-10 membered heterocyclic group”, “5-10 membered heterocyclic group”, “5-6 membered heterocyclic group”, “5-8 membered heterocyclic group”, “6-10 membered heterocyclic group” ], “9-10 membered heterocyclic group” and the like. The above heteroatoms include N, O and S atoms, etc., and C, N and S atoms may be oxoated. Examples include furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1,4-dioxacyclohexadienyl, 2H-1, 2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1, 2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,3,4-triazinyl, 1,2,4,5-tetrazinyl, oxacycloheptatrienyl, thiacycloheptatri Enil, azacyclohept Tatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, 1,4-dihydro-1,4-diazacyclooctatrienyl, 1,4-dioxacyclooctatrienyl, benzofuryl, benzo Isofuryl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyrida Examples include, but are not limited to, dinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenoxazinyl, pteridinyl, purinyl, naphthyridinyl, phenazinyl, phenothiazinyl, 2,3-dihydrobenzo [b] [1,4] dioxane, and the like. .

  In this specification, rights are sought for a method for preparing the compound of formula (I), and the compound of formula (I) is synthesized by the following process and / or other techniques already known in the art. However, it is not limited to the following method.

(1) Preparation of intermediate 1:
At a low temperature (for example, −15 to 5 ° C.), 1.5 molar equivalents of trifluoroacetic acid are placed in a reaction flask, and dichloromethane in which 3.0 molar equivalents of triethylsilane is dissolved is added and stirred to react. Next, a dichloromethane solution containing 1 molar equivalent of raw material 1 and 1.1 molar equivalent of raw material 2 is slowly added dropwise to the reaction flask. After completion of the dropwise addition, the reaction is further carried out while maintaining a low temperature (for example, −15 to 5 ° C.), the pH is adjusted to alkaline with a sodium hydroxide solution, a sodium chloride solution is added, and the mixture is extracted with dichloromethane. The extract is dried over anhydrous sodium and concentrated to give a solid. Wash with diethyl ether to give intermediate 1.

(2) Preparation of intermediate 2:
Dissolve 1 molar equivalent of Intermediate 1 in DMF, add 2 equivalents of alkali (e.g., cesium carbonate, potassium carbonate, etc.) and stir at 5 to 30 ° C., then add 1.1 equivalents of raw material 3 for several hours. React. After completion of the reaction, the mixture is filtered, water is added to the filtrate, and the mixture is extracted with ethyl acetate. The extract is washed with water, saturated sodium chloride solution, rotoevaporated and dried. The residue is fractionated on a silica gel column to obtain intermediate 2.

(3) Preparation of compound of formula (I):
Add a 1 molar equivalent of Intermediate 2 to a dry reaction vessel, dissolve in dichloromethane, add 3 molar equivalents of triethylamine, and dissolve a dichloromethane solution in which 1.1 equivalents of raw material 4 is dissolved at a low temperature (for example, -15 to 5 ° C). After slowly adding dropwise, the reaction is continued for 1 hour while keeping the temperature low. The reaction is stirred overnight at room temperature. Filter, add aqueous sodium bicarbonate and extract with dichloromethane. The extract is rotoevaporated to dryness and fractionated on a column to give the compound of formula (I).

(1) Preparation of intermediate 1:
Put 1 molar equivalent of raw material 1 and 1.3 molar equivalent of raw material 2 into a dried flask, dissolve in toluene and triethylamine, and use (Ph ₃ P) ₂ PdCl ₂ and copper (I) iodide as catalysts, and in a nitrogen atmosphere The reaction is heated for an hour. After cooling, spin-evaporate and dry, and fractionate with a column to obtain Intermediate 1.

(2) Preparation of intermediate 2:
1 molar equivalent of the intermediate is dissolved in DMF, 2 molar equivalents of alkali (eg, cesium carbonate, potassium carbonate, etc.) is added, and the mixture is stirred at 5 to 30 ° C. for reaction. Add 1.1 molar equivalent of raw material 3 and react for several more hours. After completion of the reaction, the mixture is filtered, water is added to the filtrate, and the mixture is extracted with ethyl acetate. The extract is washed with water, saturated sodium chloride solution, rotoevaporated to dryness and fractionated on a silica gel column to give intermediate 2.

(3) Preparation of compound of formula (I):
1 mol equivalent of Intermediate 2 is put in a dry reaction vessel, dissolved in dichloromethane, 3 mol equivalent of triethylamine is added, and then 1.1 mol equivalent of raw material 4 is dissolved at low temperature (for example, -15 to 5 ° C). The solution is slowly added dropwise. After completion of the dropwise addition, the mixture is further reacted at a low temperature (for example, -15 to 5 ° C) for 1 hour. Stir overnight at 5-30 ° C. Filter, add aqueous sodium bicarbonate and extract with dichloromethane. The extract is rotoevaporated to dryness and fractionated on a column to give the compound of formula (I).

(1) Preparation of intermediate 1:
1 molar equivalent of raw material 1 and 1 molar equivalent of raw material 2 are placed in toluene, 1.2 equivalents of alkali (such as cesium carbonate) is added, a catalyst (such as hexadecyltributylphosphonium bromide) is added, and the mixture is heated for several hours. After the reaction is complete, cool, add water and extract with diethyl ether. The extract is washed with water, the organic phase is rotoevaporated to dryness and purified by preparative liquid chromatography to give intermediate 1.

(2) Preparation of the compound of formula (I):
Add 1 molar equivalent of Intermediate 1 to a dry reaction vessel, dissolve in dichloromethane, add 3 molar equivalents of triethylamine, and dissolve 1.1 molar equivalent of raw material 3 at low temperature (e.g., -15 to 5 ° C). Is slowly added dropwise. After completion of the dropwise addition, the mixture is further reacted for 1 hour at a low temperature (for example, -15 to 5 ° C). Stir overnight at 5-30 ° C. Filter, add aqueous sodium bicarbonate and extract with dichloromethane. The extract is rotoevaporated to dryness and fractionated on a column to give the compound of formula (I).

In the above reaction formula, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , W, X, Y, L ¹ , L ² , L ³ , A, and B are as defined above. If necessary, the functional group required for protection can be protected, and then the protective group can be removed by a conventional method. If necessary, the reaction solvent can be changed depending on the properties of the compound. If necessary, depending on the nature of the compound, the process of making a compound can be omitted and / or added.

  The pharmaceutically acceptable salts of any of the above compounds in the present specification include alkali metal salts (for example, sodium salts, potassium salts, lithium salts), alkaline earth metal salts (for example, calcium salts, magnesium salts, etc.), Other metal salts (for example, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.), inorganic alkali salts (for example, ammonium salts), organic alkali salts (for example, tert-octylamine salts, dibenzylammonium salts) , Morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine Salt, diethanolamine salt, N-benzyl -Phenylethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt.When the compound according to the present invention is alkaline, it is pharmaceutically acceptable non-toxic including inorganic acid and organic acid. A salt can be produced from an acid, such as a hydrohalide salt (for example, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.) ), Inorganic acid salts (eg, nitrates, perchlorates, sulfates, phosphates, etc.), lower alkyl sulfonates (eg, methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, etc.), Aryl sulfonates (eg benzene sulfonate, toluene sulfonate, etc.), organic acid salts (eg acetate, malate, fumarate, succinate, citrate Salts, tartrate, oxalate, maleate, etc.), amino acid salts (eg glycine salt, trimethylglycine salt, arginine salt, ornithine salt, glutamate, aspartate, etc.) etc. Compounds of the invention Can have one, two or three cation forming cations, depending on the number of carboxy functional groups and the valence of the cation. It will be apparent to those skilled in the art that is formed at the free carboxy group of the compound and made by conventional methods.

  The present invention also includes stereoisomers of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Since the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a chiral molecule, it can also exist as an optical isomer. Accordingly, optical isomers and mixtures thereof are also included in the present invention. When the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes a double bond or a small cyclic structure, the rotation of the bond between atoms in the double bond or the ring is spatially inhibited. By doing so, different spatial arrangements are possible, resulting in stereoisomers (also called cis-trans isomers). The present invention also includes cis-trans isomers and mixtures thereof. The present invention also includes stereoisomers (also referred to as conformational isomers) generated by spatially changing the arrangement position of atoms or atomic groups resulting from rotation of a single bond of a compound, and mixtures thereof. Is also included.

The compound represented by the formula (I) of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof can be prepared into a pharmaceutically acceptable drug formulation together with one or more kinds of drug carriers. And can be administered to patients in need of oral and other methods. In the case of oral administration, it can be prepared into ordinary solid preparations (for example, tablets, capsules, pills, granules, etc.) together with ordinary fillers, adhesives, disintegrants, lubricants and diluents; In cases other than administration, it can be prepared into an injection (eg, injection solution, sterile powder for injection, concentrated solution for injection, etc.). When preparing an injection, it can be prepared by a known method, and no additive may be added, or an additive may be added depending on the nature of the drug. These production methods are known methods or are obvious to those skilled in the art. For example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 16 th, Ed., Referring to the methods described in 1980.

  The present invention further relates to a compound of the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof, for the preparation of a medicament for the treatment and / or prevention of diseases related to CRTH2 activity. Also provides use. Diseases related to CRTH2 activity include, for example, asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronic rubella, basophilia, psoriasis, These include eczema, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, arthritis or chronic obstructive pulmonary disease (COPD).

  The “treatment” in the present invention means to alleviate, ameliorate, eliminate or reduce a sign or symptom associated with a disease or disease.

  The term “prevention” in the present invention means preventing or delaying the occurrence or development of a disease or disease, or preventing or delaying a sign or medical condition associated with the disease or disease.

  The present invention further provides a pharmaceutical composition comprising a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof, and one or more therapeutically active substances. . The above therapeutically active substances are TNF-α inhibitors, COX-1 / COX-2 inhibitors, COX-2 inhibitors, glucocorticoids, interleukin inactivating antibodies, chemokine receptor modulators, histamine H1 receptor antagonists / Antihistamine, leukotriene D4 receptor antagonist, leukotriene receptor antagonist, VLA-4 antagonist, corticosteroid, corticosteroid, β2-agonist, theophylline, leukotriene biosynthesis inhibitor, cyclooxygenase 2 inhibitor, PDE4 inhibitor Selected from drugs, opioid analgesics, anticoagulants, β-blockers, β-adrenergic receptor agonists, ACE inhibitors or HMG-CoA reductase inhibitors.

  The “composition” in the present invention is any mixture in which an active ingredient and a constituent carrier are produced by inert complexation or assembly, decomposition of one or more kinds of ingredients, or other reaction or interaction. is there. Therefore, the drug composition in the present invention includes any composition produced by mixing the compound represented by the general formula (I) and one or more pharmaceutically acceptable excipients.

  Next, the effects of the compounds of the present invention will be further explained with reference to the pharmacological activity test of some compounds of the present invention. Other compounds of the present invention are also described below with some of the compounds of the present invention. It should not be understood that the compound of the present invention has the same effect and has only the following effect.

Test Example 1 Pharmacological activity of the compound of the present invention in vitro Sample Ramatroban (commercially available);
The compound of the present invention (prepared by the method of Examples).

Test Method This test was commissioned to Nanjing Jinzui Biological Technology Co., Ltd. and carried out by the calcium flow measurement method. The method and results are as follows.
The sample is accurately weighed and dissolved in DMSO to prepare a 50 mM solution. Then dilute to 50 μM with 20 mM HEPES buffer, pH 7.4. Here, the maximum compound concentration is 10000 nM. Dilute to 10 consecutive concentrations in a 3-fold series.

FLIPR detection (Fluorometric Imaging Plate Reader)
Place 20 μL of cell solution containing 20000 CHO-K1 / CRTH2 / Gα15 in a 384-well black plate, incubate for 18 h at 37 ° C, 5% CO ₂ , and then add 20 μL of the stain in the FLIPR® Calcium 4 assay kit. In addition, 10 μL of the compound solution is further added and incubated at 37 ° C. for 60 minutes, and then incubated at room temperature for 15 minutes. Within 20 seconds, add PGD2 HEPES buffer with EC ₈₀ concentration of agonist PGD2 and detect fluorescence values for 21-120 seconds.

Data processing ΔRFU (relative fluorescence intensity) = maximum fluorescence value for 21 to 120 seconds−1 average value of fluorescence values for 1 to 20 seconds Inhibition rate = {1− (ΔRFU _compound− ΔRFU _background ) / (ΔRFU _{agonist control−} ΔRFU _Background )} x 100
Calculate the IC50 of each compound by the inhibition rate (ie, the concentration of test compound required to inhibit CRTH2 receptor activation induced by EC ₈₀ concentration of PGD ₂ by 50%)

以上の表1の結果から、本発明化合物のCRTH2受容体に対する拮抗作用はラマトロバンより顕著である。 Test results and discussion

From the results in Table 1 above, the antagonistic action of the compound of the present invention on the CRTH2 receptor is more remarkable than that of ramatroban.

Test Example 2 In Vivo pharmacological activity (oral administration)
Sample Compound of the present invention (prepared by the method of Example)

Test Method This test was commissioned to Tatetsu Biopharmaceutical Technology (Shanghai) Co., Ltd., and a test was conducted to verify the therapeutic effect of the compound of the present invention on the OVA-induced mouse asthma model. Specific test methods and results are as follows.
After the female BALB / c mice are handled, they are randomly divided into a control group, a model group and a sample group according to body weight. See Table 2 for details on animal groupings, drug doses and volumes. On the 1st and 14th day, the model group and the sample group caused allergies by intraperitoneally injecting OVA (ovalbumin) solution (containing 20 μg of OVA and 2 mg of aluminum potassium sulfate) at a dose of 0.1 mL / animal. Inject PBS (phosphate buffer). On days 28, 29 and 30, 1% OVA is administered by nebulizer and induced for 30 min. PBS is used instead of 1% OVA for the control group. On day 27, 28, 29, 30, 31 the animals are orally administered drugs or solvents. The control group receives the solvent twice daily, 1 h before PBS inhalation and 7 h after inhalation. The model group is dosed with the solvent twice daily, 1 h before induction of OVA inhalation and 7 h after induction. Sample groups are administered twice daily, 1 h before induction of OVA inhalation and 7 h after induction. Immediately after the animal was sacrificed on day 32, the lungs were immediately perfused and washed from the bronchi with 0.5 mL of PBS (including 1% FBS), washed twice more, combined with the washings, and the centrifuged cells were added to 1.5 ml. Suspend in PBS (containing 1% FBS). Count cells in bronchoalveolar lavage fluid.

Conclusion As can be seen from the results in Table 3, Compound 9 significantly reduces the total number of leukocytes, especially the number of eosinophils, and has a good therapeutic effect on OVA-induced mouse asthma inflammation.

  Hereinafter, the content of the present invention will be described in more detail using specific examples, but the present invention should not be understood to be limited to the following examples.

Example 1 Preparation of 2- [1- [4- (2-naphthamido) benzyl] -2-methyl-1H-indol-3-yl] acetic acid (Compound 1)

1. Preparation of methyl 2- (2-methyl-1H-indol-3-yl) acetate
2- (2-Methyl-1H-indol-3-yl) acetic acid (11.7 g, 61.84 mmol) is weighed into 100 mL of methanol, 0.7 mL of concentrated hydrochloric acid is added dropwise, and the mixture is reacted at 70 ° C. for 4 hours. Cool, rotary evaporate, extract with ethyl acetate and wash twice with an aqueous solution of NaHCO ₃ . The organic phase is rotoevaporated to dryness to give a brown solid (11.4 g, 90.7% yield).

2. Preparation of methyl 2- [2-methyl-1- (4-nitrobenzyl) -1H-indol-3-yl] acetate methyl 2- (2-methyl-1H-indol-3-yl) acetate in 100 mL of toluene (4.9g, 24.1mmol), p-nitrobenzyl bromide (5.18g, 24.0mmol), cesium carbonate (9.38g, 28.8mmol), hexadecyltributylphosphonium bromide (1.58g, 3.1mmol) were added, React at 110 ° C for 6 hours. After the reaction is complete, cool, add water and extract with diethyl ether. The extract is washed with water, rotary evaporated and purified by preparative chromatography to give the compound (300 mg, 3.7% yield).

3. Preparation of methyl 2- [1- (4-aminobenzyl) -2-methyl-1H-indol-3-yl] acetate In a dry flask, 2- [2-methyl-1- (4-nitrobenzyl)- 1H-Indol-3-yl] methyl acetate (300 mg, 0.887 mmol) is added, dissolved in 10 mL of methanol, and 20 mg of 10% Pd / C is added and reacted in hydrogen gas for 3 hours. After completion of the reaction, the mixture is filtered, the solid is washed with methanol, and the filtrate is rotary evaporated to obtain a solid (260 mg, yield 95.0%).

4. Preparation of methyl 2- [1- [4- (2-naphthamido) benzyl] -2-methyl-1H-indol-3-yl] acetate 2- [1- (4aminobenzyl) -2 in a dry flask -Methyl-1Hindol-3-yl] Methyl acetate (260 mg, 0.843 mmol) was added, dissolved with 10 mL of dichloromethane, triethylamine (0.36 mL, 2.59 mmol) was added, and then 2-naphthoyl chloride was slowly added in an ice bath. (195 mg, 1.02 mmol) is added and allowed to react for 1 hour in an ice bath. Stir at room temperature for 3 days. A sodium hydrogen carbonate solution is added to quench the reaction, followed by extraction with dichloromethane. Spin to dryness and fractionate on a column to give a white solid (150 mg, 38.4% yield).

5. Preparation of 2- [1- [4- (2-naphthamido) benzyl] -2-methyl-1H-indol-3-yl] acetic acid In a dry flask, 2- [1- [4- (2-naphthamido) [Methyl] [benzyl] -2-methyl-1H-indol-3-yl] acetate (150 mg, 0.324 mmol), add lithium hydroxide monohydrate (55 mg, 1.31 mmol), 3 mL of tetrahydrofuran and 3 mL of water at room temperature Stir for 2 hours. After detecting the end of the reaction by TLC, the solvent is removed by rotary evaporation and adjusted to pH = 3-4 with 2N HCl solution. Extract with ethyl acetate and rotary evaporation to give a white solid (80 mg). Recrystallize with ethyl acetate to obtain the pure product (51 mg, 35.2% yield).
LC-MS (M + H): 449.2
¹ H-NMR (d ₆ -DMSO, 400 MHz): δ 10.40 (1H, s), 8.52 (1H, s), 8.08-7.94 (4H, m), 7.70 (2H, d), 7.65-7.56 (2H , m), 7.45 (1H, d), 7.38 (1H, d), 7.08-6.95 (4H, m), 5.37 (2H, s), 3.63 (2H, s), 2.32 (3H, s).

Example 2 Preparation of 2- [3- [4- (2-naphthamido) benzyl] -2-methyl-1H-indol-1-yl] acetic acid (Compound 2)

1. Preparation of 2-methyl-3- (4-nitrobenzyl) -1H-indole A flask in an ice bath was charged with trifluoroacetic acid (6.824 g, 60 mmol), triethylsilane (13.9 g, 120 mmol) and 20 mL dichloromethane. After stirring for 5 min, a dichloromethane solution containing 2-methyl-1H-indole (5.24 g, 40 mmol) and p-nitrobenzaldehyde (6.67 g, 44 mmol) was slowly added dropwise, and the reaction was continued for 1 hour while maintaining the temperature. Let Adjust the pH to 8-9 with 2M sodium hydroxide solution, add aqueous sodium chloride solution, and extract with dichloromethane. The extract is dried over anhydrous sodium and concentrated to give a brown solid. Wash with diethyl ether to obtain a yellow powdered solid (4.3 g, 40.3% yield).

2. Preparation of ethyl 2- [2-methyl-3- (4-nitrobenzyl) -1H-indol-1-yl] acetate
2-Methyl-3- (4-nitrobenzyl) -1H-indole (4.0 g, 15 mmol) is weighed and dissolved in 30 mL of DMF, cesium carbonate (9.77 g, 30 mmol) is added, and the mixture is stirred at room temperature for 15 minutes. Add ethyl bromoacetate (2.755g, 16.5mmol) and react at room temperature for 3 hours. After completion of the reaction, the mixture is filtered, water is added to the filtrate, and the mixture is extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride solution, spin-dried and fractionated on a silica gel column (petroleum ether) to give a yellow solid (2.7 g, yield 51.1%).

3. Preparation of ethyl 2- [3- (4-aminobenzyl) -2-methyl-1H-indol-1-yl] acetate 2- [2-methyl-3- (4-nitrobenzyl)- 1H-Indol-1-yl] ethyl acetate (2.7 g, 7.66 mmol) is added and dissolved by adding 30 mL of methanol, and 300 mg of 10% Pd / C is added, and the reaction is allowed to proceed overnight in hydrogen gas. After completion, it is filtered and the solid is washed with methanol. The filtrate is rotoevaporated to give a white solid (2.28 g, 92.3% yield).

4. Preparation of 2- [3- [4- (2-naphthamido) benzyl] -2-methyl-1H-indol-1-yl] ethyl acetate 2- [3- (4-aminobenzyl)- 2-Methyl-1H-indol-1-yl] ethyl acetate (1.644 g, 5.1 mmol) is added, dissolved in 30 mL of dichloromethane, triethylamine (2.13 mL, 15.3 mmol) is added, and 2-naphthoyl chloride (1.067 is added in an ice bath). g, 5.6 mmol) in dichloromethane is slowly added dropwise, and after completion of the addition, the mixture is allowed to react in an ice bath for 1 hour. Stir overnight at room temperature. Filter, add aqueous sodium bicarbonate and extract with dichloromethane. The extract is rotoevaporated to dryness and fractionated on a column to give a white solid (0.53 g, 21.8% yield).

5. Preparation of 2- [3- [4- (2-naphthamido) benzyl] -2-methyl-1H-indol-1-yl] acetic acid sequentially into a dry flask, 2- [3- [4- (2- Naphthoamido) benzyl] -2-methyl-1H-indol-1-yl] ethyl acetate (530 mg, 1.11 mmol), lithium hydroxide monohydrate (140 mg, 3.34 mmol), tetrahydrofuran 5 mL, methanol 5 mL, water 10 mL Stir at room temperature for 1 hour. After detecting the end of the reaction with TLC, the solvent is rotoevaporated, and the pH is adjusted to 3-4 with 2N HCl solution to precipitate a solid. The solid is washed sequentially with ethyl acetate, dichloromethane and acetonitrile to give a white solid (100 mg, 20.1% yield).
LC-MS (M + H): 449.2
¹ H-NMR (d ₆ -DMSO, 400 MHz): δ 10.31 (1H, s), 8.53 (1H, s), 8.05 (1H, dd), 8.02-7.96 (3H, m), 7.65 (2H, d ), 7.63-7.57 (2H, m), 7.32 (1H, d), 7.22-7.15 (3H, m), 6.95 (1H, t), 6.86 (1H, t), 4.41 (2H, s), 3.99 ( 2H, s), 2.33 (3H, s).

Example 3 Preparation of 2- [2-methyl-3- [4- [4- (trifluoromethyl) benzamido] benzyl] -1H-indole-1-l] acetic acid (Compound 3)

1. Preparation of 2- [2-methyl-3- [4- [4- (trifluoromethyl) benzamido] benzyl] -1H-indol-1-yl] ethyl acetate 2- [3- (4 -Aminobenzyl) -2-methyl-1H-indol-1-yl] ethyl acetate (1.0 g, 3.11 mmol) was added, dissolved in 15 mL of dichloromethane, triethylamine (1.3 mL, 9.34 mmol) was added, A dichloromethane solution in which trifluoromethylbenzoyl chloride (0.649 g, 3.11 mmol) is dissolved is slowly added dropwise, followed by further reaction in an ice bath for 4 hours. Filter, add aqueous sodium bicarbonate and extract with dichloromethane. The extract is rotoevaporated and fractionated on a column to give a white solid (1.15 g, 74.9% yield).

2. Preparation of 2- [2-methyl-3- [4- [4- (trifluoromethyl) benzamido] benzyl] -1H-indol-1-yl] acetic acid In a dry flask, 2- [2-methyl-3 -[4- [4- (Trifluoromethyl) benzamido] benzyl-1H-indol-1-yl] ethyl acetate (600 mg, 1.21 mmol) was added, lithium hydroxide monohydrate (153 mg, 3.64 mmol), tetrahydrofuran Add 10 mL, 10 mL of methanol, and 10 mL of water, and stir at room temperature for 1 hour. After detecting the end of the reaction by TLC, rotary evaporation is performed and the solvent is removed. Adjust the pH to 3-4 with 2N HCl solution and filter. The solid is washed with 20 mL of methanol to give a white solid (480 mg, 85.1% yield).
LC-MS (M + H): 467.2
¹ H-NMR (d ₆ -DMSO, 400 MHz): δ 10.36 (1H, s), 8.10 (2H, d), 7.87 (2H, d), 7.60 (2H, d), 7.33 (1H, d), 7.25 (1H, d), 7.18 (2H, d), 6.98 (1H, t), 6.89 (1H, t), 4.72 (2H, s), 3.99 (2H, s), 2.32 (3H, s).

Example 4 Preparation of 2- [3- [4- (3,4-dichlorobenzamido) benzyl] 2-methyl-1H-indol-1-yl] acetic acid (Compound 4)

1. Preparation of ethyl 2- [3- [4- (3,4-dichlorobenzamido) benzyl] -2-methyl-1H-indol-1-yl] acetate In a dry flask, 2- [3- (4-amino (Benzyl) -2-methyl-1H-indol-1-yl] ethyl acetate (1.0 g, 3.11 mmol) is added, dissolved in 15 mL of dichloromethane, triethylamine (1.3 mL, 9.3 mmol) is added, and 3,4- A dichloromethane solution in which dichlorobenzoyl chloride (0.652 g, 3.11 mmol) is dissolved is slowly added dropwise, followed by further reaction for 4 hours in an ice bath. Filter, add aqueous sodium bicarbonate and extract with dichloromethane. The extract is rotoevaporated to dryness and fractionated on a column to give a white solid (1.23 g, 79.7% yield).

2. Preparation of 2- [3- [4- (3,4-dichlorobenzamido) benzyl] -2-methyl-1H-indol-1-yl] acetic acid In a dry flask, 2- [3- [4- (3 , 4-Dichlorobenzamido) benzyl] -2-methyl-1H-indol-1-yl] ethyl acetate (691 mg, 1.39 mmol), lithium hydroxide monohydrate (176 mg, 4.19 mmol), tetrahydrofuran 10 mL, methanol Add 10 mL and 10 mL of water, and stir at room temperature for 1 hour to react. After detecting the end of the reaction by TLC, rotary evaporation is performed and the solvent is removed. Adjust the pH to 3-4 with 2N HCl solution and filter. The solid is washed with 20 mL of methanol to give a white solid (551 mg, 84.9% yield).
LC-MS (M + H): 467.1
¹ H-NMR (d ₆ -DMSO, 400 MHz): δ 10.29 (1H, s), 8.16 (1H, d), 7.89 (1H, dd), 7.78 (1H, d), 7.58 (2H, d), 7.34 (1H, d), 7.28 (1H, d), 7.18 (2H, d), 7.00 (1H, t), 6.91 (1H, t), 4.83 (2H, s), 3.99 (2H, s), 2.32 (3H, s).

Example 5 Preparation of 2- [3- (4- (2-naphthamido) benzyl) -1H-indazol-1-yl] acetic acid (Compound 5)

1． Preparation of (2-iodophenyl) hydrazine
o-Iodoaniline (21.9 g, 100 mmol) is dissolved in 40 mL of concentrated hydrochloric acid, 35 mL (6.9 g, 100 mmol) of sodium nitrite aqueous solution is added dropwise at 0 ° C., and the mixture is stirred at 0 ° C. for 30 minutes, and then SnCl ₂ · 2H ₂ A solution of O (64.7 g, 300 mmol) dissolved in 70 mL of concentrated hydrochloric acid is slowly added dropwise and allowed to react for 3 hours. Filter and wash the resulting white solid with saturated sodium chloride solution and then with a mixture of petroleum ether and diethyl ether (1: 1). Next, the solid is adjusted to be alkaline with a sodium hydroxide solution and filtered to remove solid impurities. The aqueous phase is extracted several times with dichloromethane and the organic phases are combined. The organic phase is rotary evaporated to dryness to give a colorless oil (10.3 g, 44.0% yield).

2. Preparation of 3- (4-nitrobenzyl) -1H-indazole (2-Iodophenyl) hydrazine (10.3 g, 44 mmol), 100 mL of toluene, 50 mL of triethylamine, p-nitrophenylacetylene (8.41 g, 57.2) mmol), (Ph ₃ P) ₂ PdCl ₂ (500 mg) and cuprous iodide (250 mg) are added and reacted at 110 ° C. in a nitrogen atmosphere for 4.5 hours. After cooling and rotary evaporation of the solvent, it is fractionated on a column to give a red liquid (2.15 g, 8.50 mmol, 19.3% yield).

3. Preparation of ethyl 2- [3- (4-nitrobenzyl) -1H-indazol-1-yl] acetate 3- (4-nitrobenzyl) -1H-indazole (2.15 g, 8.49 mmol) in a dry flask, DMF10mL, ethyl bromoacetate (1.70g, 10.2mmol) and cesium carbonate (5.54g, 17.0mmol) are added and allowed to react overnight at room temperature. Separation by column gives a red solid (1.4 g, 48.5% yield).

4. Preparation of ethyl 2- [3- (4-aminobenzyl) -1H-indazol-1-yl] acetate
2- [3- (4-Nitrobenzyl) -1H-indazol-1-yl] ethyl acetate (1.3 g, 3.83 mmol) is dissolved in 40 mL of methanol, Pd-C (20 mg) is added, and nitrogen gas is added at room temperature. React overnight. Filter to remove solids. After rotary evaporation of the solvent, a white solid is obtained by preparative chromatography (630 mg, 53.3% yield).

5. Preparation of ethyl 2- [3- [4- (2-naphthamido) benzyl] -1H-indazol-1-yl] acetate
Dissolve ethyl 2- [3- (4-aminobenzyl) -1H-indazol-1-yl] acetate (630 mg, 2.04 mmol) in 20 mL of dichloromethane, add triethylamine (0.85 mL, 6.11 mmol), and add 2- A dichloromethane solution containing naphthoyl chloride (428 mg, 2.25 mmol) is slowly added dropwise and allowed to react in an ice bath for 3 hours. Quench the reaction by adding sodium hydrogen carbonate solution and extract with ethyl acetate. The extract is rotoevaporated and fractionated on a column to give a white solid (850 mg, 89.7% yield).

6. Preparation of 2- [3- [4- (2-naphthamido) benzyl] -1H-indazol-1-yl] acetic acid
Dissolve ethyl 2- [3- [4- (2-naphthamido) benzyl] -1H-indazol-1-yl] acetate (575 mg, 1.24 mmol) in a mixture of 10 mL of tetrahydrofuran and 3 mL of methanol. 10 mL of an aqueous solution in which lithium oxide monohydrate (333 mg, 7.93 mmol) is dissolved is added and reacted at room temperature for 3 hours. After detecting the end of the reaction with TLC, water is added, and the pH is adjusted to be acidic with dilute hydrochloric acid to precipitate a solid. After filtration, it is dried to give a white solid (470 mg, 1.08 mmol, 87.1% yield).
LC-MS (M + H): 436.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.37 (s, 1H), 8.54 (s, 1H), 8.09-7.95 (m, 4H), 7.71 (d, 2H), 7.66-7.57 (m, 3H), 7.56 (d, 1H), 7.34 (td, 1H), 7.29 (d, 2H), 7.07 (td, 1H), 5.20 (s, 2H), 4.25 (s, 2H).

Example 6 Preparation of 2- [3- [4- (4-Chlorobenzamido) benzyl] -2-methyl-1H-indol-1-yl] acetic acid (Compound 6)

1. Preparation of ethyl 2- [3- [4- (4-chlorobenzamido) benzyl] -2-methyl-1H-indol-1-yl] acetate In a dry flask, 2- [3- (4-aminobenzyl ) -2-Methyl-1H-indol-1-yl] ethyl acetate (1.0 g, 3.10 mmol) was added, dissolved in 15 mL of dichloromethane, triethylamine (1.3 mL, 9.34 mmol) was added, and 4-chlorobenzoyl chloride was added in an ice bath. A dichloromethane solution in which (0.544 g, 3.11 mmol) is dissolved is slowly added dropwise, followed by further reaction in an ice bath for 4 hours. Filter, add sodium bicarbonate solution and extract with dichloromethane. The extract is rotoevaporated and fractionated on a column to give a white solid (0.580 g, 40.6% yield).

2. Preparation of 2- [3- [4- (4-Chlorobenzamido) benzyl] -2-methyl-1H-indol-1-yl] acetic acid In a dry flask, 2- [3- [4- (4- Chlorobenzamido) benzyl] -2-methyl-1H-indol-1-yl] ethyl acetate (580 mg, 1.26 mmol), lithium hydroxide monohydrate (159 mg, 3.79 mmol), tetrahydrofuran 10 mL, methanol 10 mL, water Add 10 mL and stir at room temperature for 1 hour. After detecting the end of the reaction by TLC, the solvent is removed by rotary evaporation. Adjust to pH 3-4 with 2N HCl solution and filter. The solid is washed with 20 mL of methanol to give a white solid (523 mg, 95.9% yield).
LC-MS (M + H): 433.2
¹ H-NMR (d ₆ -DMSO, 400 MHz): δ 10.21 (1H, s), 7.93 (2H, d), 7.59 (2H, d), 7.57 (2H, d), 7.35 (1H, d), 7.31 (1H, d), 7.17 (2H, d), 7.01 (1H, t), 6.92 (1H, t), 4.93 (2H, s), 3.99 (2H, s), 2.32 (3H, s).

Example 7 Preparation of 2- [3- [4- (2-naphthamido) benzyl] -2-ethyl-1H-indol-1-yl] acetic acid (Compound 7)

1. Preparation of 2-methyl-1H-indole In a flask in an ice bath, 2-methylindole (5 g, 38.1 mmol), anhydrous diethyl ether 300 mL, 2.4 M n-BuLi (47.5 mL, 114 mmol) and potassium tert-butoxide ( 8.5g, 75.8mmol) and stir for 30 minutes at room temperature in a nitrogen atmosphere. It is then cooled to -70 ° C. and iodomethane (10.245 g, 72.2 mmol) is added dropwise and allowed to react for another 2 hours. After completion of the reaction, the temperature is raised to −40 ° C., 2 mL of water is added, and the temperature is raised to room temperature. The reaction solution is poured into water, adjusted to pH 6 and extracted with diethyl ether. Dry to obtain a solid (3.74 g, 67.7% yield).

2. Preparation of 2-ethyl-3- (4-nitrobenzyl) -1H-indole Place trifluoroacetic acid (4.4 g, 38.6 mmol), triethylsilane (9.02 g, 77.6 mmol), and 15 mL of dichloromethane in a flask in an ice bath. After stirring for 5 minutes, a dichloromethane solution containing 2-ethyl-1H-indole (3.74 g, 25.8 mmol) and p-nitrobenzaldehyde (4.29 g, 28.4 mmol) was slowly added dropwise, and the temperature was maintained. Let react for 1 hour. Adjust the pH to 8-9 with 2M sodium hydroxide solution, add aqueous sodium chloride solution, and extract with dichloromethane. The extract is dried over anhydrous sodium sulfate and concentrated to give a brown solid. Wash with a small amount of diethyl ether to give a yellow powdered solid (3 g, 41.5% yield).

3. Preparation of ethyl 2- [2-ethyl-3- (4-nitrobenzyl) -1H-indol-1-yl] acetate
2-Ethyl-3- (4-nitrobenzyl) -1H-indole (3.0 g, 10.7 mmol) is weighed and dissolved in 30 mL of DMF, cesium carbonate (6.98 g, 21.4 mmol) is added, and the mixture is stirred at room temperature for 15 minutes. Add ethyl bromoacetate (1.97 g, 11.8 mmol) and react at room temperature for 10 hours. Filter, add water to the filtrate and extract with ethyl acetate. The extract is washed with water, saturated sodium chloride solution, rotoevaporated and purified by preparative chromatography to give a yellow solid (350 mg, yield 8.97%).

4. Preparation of ethyl 2- [3- (4-aminobenzyl) -2-ethyl-1H-indol-1-yl] acetate 2- [2-ethyl-3- (4-nitrobenzyl)- [1H-Indol-1-yl] ethyl acetate (350 mg, 0.96 mmol) is added, dissolved in 10 mL of methanol, 50 mg of 10% Pd / C is added, and the mixture is reacted in dry hydrogen gas for 1 hour. After completion of the reaction, the mixture is filtered and the solid is washed with methanol. The filtrate is rotoevaporated and dried to give a white solid (288 mg, 89.6% yield).

5. Preparation of ethyl 2- [3- [4- (2-naphthamido) benzyl] -2-ethyl-1H-indol-1-yl] acetate 2- [3- (4-aminobenzyl)- 2-ethyl-1H-indol-1-yl] ethyl acetate (288 mg, 0.86 mmol) was added, dissolved in 7 mL of dichloromethane, triethylamine (0.36 mL, 2.59 mmol) was added, and 2-naphthoyl chloride (163 mg) was slowly added in an ice bath. , 0.86 mmol) in 2 mL of dichloromethane is added dropwise, followed by further reaction in an ice bath for 1 hour and stirring overnight at room temperature. Add water, extract with dichloromethane, rotoevaporate to dryness to obtain the crude product. Furthermore, it is washed with a small amount of acetonitrile to obtain a yellow solid (340 mg, yield 80.2%).

6. Preparation of 2- [3- [4- (2-naphthamido) benzyl] -2-ethyl-1H-indol-1-yl] acetic acid In a dry flask, 2- [3- [4- (2-naphthamido) [Benzyl] -2-ethyl-1H-indol-1-yl] ethyl acetate (340 mg, 0.69 mmol), lithium hydroxide monohydrate (117 mg, 2.79 mmol), tetrahydrofuran (5 mL) and water (5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Stir. After detecting the end of the reaction with TLC, 10 mL of water is added, and the pH is adjusted to 5 with 2N HC1 solution to precipitate a solid. Suction filtered and washed with dichloromethane to give a pale yellow solid (240 mg, 75.2% yield).
LC-MS (M + H): 463.2
¹ H-NMR (d ₆ -DMSO, 400 MHz): δ 10.34 (1H, s), 8.53 (1H, s), 8.09-7.95 (4H, m), 7.70-7.58 (4H, m), 7.35 (1H , d), 7.29 (1H, d), 7.18 (2H, d), 7.03 (1H, t), 6.94 (1H, t), 4.93 (2H, s), 4.02 (2H, s), 2.77 (2H, q), 1.06 (3H, t).

Example 8 Preparation of 2- [3- [4- (4-chlorobenzoylamino) benzyl] -1H-indazol-1-yl] acetic acid (Compound 8)

1. Preparation of ethyl 2- [3- [4- (4-chlorobenzoylamino) benzyl] -1H-indazol-1-yl] acetate
2- [3- (4-Aminobenzyl) -1H-indazol-1-yl] ethyl acetate (220 mg, 0.711 mmol) is dissolved in 20 mL of dichloromethane, triethylamine (0.15 mL, 1.08 mmol) is added, and p- Chlorobenzoyl chloride (137 mg, 0.78 mmol) is slowly added dropwise, and the end of the reaction is detected by TLC. Add water, extract with ethyl acetate and separate by preparative chromatography to give a white solid (100 mg, 31.4% yield).

2. Preparation of 2- [3- [4- (4-Chlorobenzamido) benzyl] -1H-indazol-1-yl] acetic acid
2- [3- [4- (4-Chlorobenzamido) benzyl] -1H-indazol-1-yl] ethyl acetate (100 mg, 0.223 mmol) is dissolved in 3 mL of tetrahydrofuran, and 1 mL of methanol and 3 mL of water are added to the solution. Lithium hydroxide monohydrate (47 mg, 1.12 mmol) is added and allowed to react at room temperature for 10 minutes. After detecting the end of the reaction with TLC, adjust the pH to be acidic with dilute hydrochloric acid. Add water, filter and dry to give a white solid (70 mg, 74.9% yield).
LC-MS (M + H): 420.1
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.27 (1H, s), 7.95 (2H, d), 7.64 (2H, d), 7.57 (2H, d), 7.52 (1H, d), 7.36 (1H, d), 7.29-7.20 (3H, m), 6.97 (1H, t), 4.70 (2H, s), 4.20 (2H, s).

Example 9 Preparation of 2- [1- [4- (2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 9)

1. Preparation of 3-amino-3- (2-nitrophenyl) propionic acid
o-Nitrobenzaldehyde (20.4g, 0.135mol), formic acid (20.3mL, 0.539mol) and malonic acid (18.3g, 0.176mol) were stirred at 45 ° C for 30 minutes, then ammonium formate (21.3g, 0.338mol) The mixture is heated to 70 ° C. and stirred for 1 hour. After further stirring at 95 ° C. for 4 hours, 50 mL of concentrated hydrochloric acid is added, and the mixture is stirred for 1 hour while maintaining the temperature. Cool, add 25 mL of water, wash twice with ethyl acetate (25 mL × 2), adjust the aqueous phase to a pH of 4.2 with 50% potassium hydroxide solution to precipitate a solid. Suction filtered and vacuum dried to give a yellow solid (18.33 g, 64.6% yield).

2. Preparation of 2- (1H-indazol-3-yl) acetic acid
3-Amino-3- (2-nitrophenyl) propionic acid (15 g, 71.4 mmol) was dissolved in a mixture of 85 mL of 5% sodium hydroxide solution and 5 mL of 85% hydrazine hydrate, heated to 80 ° C., Slowly add Raney nickel (25mg × 2) and react for 30 minutes. Cool and adjust the pH to about 2 with 6N hydrochloric acid to precipitate a solid. Suction filtered and vacuum dried to give a yellow solid (6.86 g, 54.5% yield).

3. Preparation of 2- (1H-indazol-3-yl) ethyl acetate
2- (1H-indazol-3-yl) acetic acid (3.9 g, 22.1 mmol) is dissolved in 100 mL of absolute ethanol and 5 mL of concentrated sulfuric acid and heated to reflux for 16 hours. Concentrate under reduced pressure to remove most of the ethanol, add 30 mL of water, and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated to give the product (3.96 g, 87.8% yield).

4. Preparation of ethyl 2- [1- (4-nitrobenzyl) -1H-indazol-3-yl] acetate
2- (1H-indazol-3-yl) ethyl acetate (408 mg, 2.0 mmol) is dissolved in 20 mL of N, N-dimethylformamide, 60% sodium hydride (96 mg, 2.4 mmol) is added, and the mixture is stirred at room temperature for 30 minutes. Then, p-nitrobenzyl bromide (475 mg, 2.2 mmol) is added and allowed to react for 1 hour. The reaction mixture is poured into ice water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, concentrated and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a yellow solid (354 mg, yield 52.1%).

5. Preparation of ethyl 2- [1- (4-aminobenzyl) -1H-indazol-3-yl] acetate
2- [1- (4-Nitrobenzyl) -1H-indazol-3-yl] ethyl acetate (340 mg, 1.04 mmol) is dissolved in 20 mL of methanol, 10% Pd / C (20 mg) is added, and nitrogen atmosphere is added. Incubate for 30 minutes. After detecting the absence of raw materials with TLC (petroleum ether: ethyl acetate = 2: 1), the solid is removed by filtration. The solvent is rotary evaporated to dryness and the resulting solid is used directly in the next reaction.

6. Preparation of 2- [1- [4- (2-naphthamido) benzyl] -1H-indazol-3-yl] ethyl acetate 2- [1- (4) is a crude product obtained by the above reaction process. -Aminobenzyl) -1H-indazol-3-yl] ethyl acetate (approximately 1.04 mmol) and triethylamine 1.4 mL were dissolved in 15 mL of dichloromethane, and 2-naphthoyl chloride (210 mg, 1.1 mmol) was slowly dissolved in an ice bath 10 mL of dichloromethane Are added dropwise and allowed to react for 16 hours at room temperature. Aqueous sodium hydrogen carbonate solution is added to quench the reaction, followed by extraction with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is removed under reduced pressure, and the residue is separated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (226 mg, yield 46.9%).

7. Preparation of 2- [1- [4- (2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid
2- [1- [4- (2-naphthamido) benzyl] -1H-indazol-3-yl] ethyl acetate (226 mg, 0.488 mmol) is dissolved in 10 mL of tetrahydrofuran, and lithium hydroxide monohydrate (62 mg) in an ice bath. , 1.48 mmol) is added, and the mixture is allowed to react at room temperature for 3 hours. After detecting the end of the reaction with TLC, water is added, and the pH is adjusted to 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (123 mg, 58% yield).
LC-MS (M + H): 436.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.42 (s, 1H), 8.53 (s, 1H), 8.08-7.94 (m, 4H), 7.76-7.68 (m, 3H), 7.66-7.55 ( m, 3H), 7.35 (t, 1H), 7.24 (d, 2H), 7.09 (t, 1H), 5.55 (s, 2H), 3.82 (s, 2H).

Example 10 Preparation of 2- [1- [4- (4-Chlorobenzamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 10)

1. Preparation of ethyl 2- [1- (4-aminobenzyl) -1H-indazol-3-yl] acetate
2- [1- (4-Nitrobenzyl) -1H-indazol-3-yl] ethyl acetate (225 mg, 0.663 mmol) is dissolved in 20 mL of methanol, 10% Pd / C (18 mg) is added, and nitrogen atmosphere is added. The mixture is reacted for 30 minutes, and TLC (petroleum ether: ethyl acetate = 2: 1) detects the absence of the raw material, followed by filtration to remove the solid. The solvent is rotary evaporated to dryness and the resulting solid is used directly in the next reaction.

2. Preparation of 2- [1- [4- (4-Chlorobenzamido) benzyl] -1H-indazol-3-yl] ethyl acetate The crude product 2- [1- (4 -Aminobenzyl) -1H-indazol-3-yl] ethyl acetate (approx. After 10 mL is added dropwise, the reaction is allowed to proceed for 16 hours at room temperature. Aqueous sodium hydrogen carbonate solution is added to quench the reaction, followed by extraction with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is rotoevaporated to dryness and the residue is fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (159 mg, 53.5% total yield combined with process 1).

3. Preparation of 2- [1- [4- (4-Chlorobenzamido) benzyl] -1H-indazol-3-yl] acetic acid
2- [1- [4- (4-Chlorobenzamido) benzyl] -1H-indazol-3-yl] ethyl acetate (159 mg, 0.355 mmol) is dissolved in 10 mL of tetrahydrofuran, and lithium hydroxide monohydrate ( 10 mL of an aqueous solution of 42 mg, 1.0 mmol) is added. After reacting at room temperature for 3 hours and detecting the end of the reaction by TLC, water is added, and the pH is adjusted to 3-4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (144 mg, 96.6% yield).
LC-MS (M + H): 420.10
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 12.62 (br s, 1H), 10.30 (s, 1H), 7.93 (d, 2H), 7.78-7.63 (m, 4H), 7.58 (d, 2H ), 7.36 (t, 1H), 7.22 (d, 2H), 7.11 (t, 1H), 5.56 (s, 2H), 3.91 (s, 2H).

Example 11 Preparation of 2- [1- [4- (2-naphthamido) benzyl] -5-fluoro-1H-indazol-3-yl] acetic acid (Compound 11)

1. Preparation of 3-amino-3- (5-fluoro-2-nitrophenyl) propionic acid
After stirring 5-fluoro-2-nitrobenzaldehyde (16.91 g, 0.10 mol), formic acid (15.2 mL, 0.40 mol) and malonic acid (13.52 g, 0.13 mol) at 45 ° C. for 30 minutes, ammonium formate (15.76 g, Add 0.25mol), heat to 70 ° C and stir for 1 hour. After further stirring at 95 ° C for 4 hours, concentrated hydrochloric acid (38 mL) is added, and the mixture is stirred for 1 hour while maintaining the temperature. Cool, add 20 mL of water, extract twice with ethyl acetate (25 mL × 2), adjust the aqueous phase with 50% potassium hydroxide solution to a pH of about 4.2, and precipitate a solid. Suction filtered and vacuum dried to give a yellow solid (15.32 g, 67.1% yield).

2. Preparation of 2- (5-fluoro-1H-indazol-3-yl) acetic acid
3-Amino-3- (5-fluoro-2-nitrophenyl) propionic acid (15.32 g, 67.1 mmol) was dissolved in a mixture of 80 mL of 5% aqueous sodium hydroxide and 5 mL of 85% hydrazine hydrate. Heat to ℃, add Raney nickel (25mg × 2) twice, react for 30 minutes, cool, adjust the pH to about 2 with 6N hydrochloric acid, and precipitate a solid. Suction filtered and vacuum dried to give a yellow solid (1.12 g, 8.6% yield).

3. Preparation of ethyl 2- (5-fluoro-1H-indazol-3-yl) acetate
2- (5-Fluoro-1H-indazol-3-yl) acetic acid (1.12 g, 5.77 mmol) is dissolved in 50 mL of absolute ethanol and 1.5 mL of concentrated sulfuric acid and heated to reflux for 16 hours. Concentrate under reduced pressure to remove most of the ethanol, add 20 mL of water, and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated to give the product (0.48 g, 37.4% yield).

4. Preparation of ethyl 2- [5-fluoro-1- (4-nitrobenzyl) -1H-indazol-3-yl] acetate
2- (5-Fluoro-1H-indazol-3-yl) ethyl acetate (0.48 g, 2.16 mmol) is dissolved in 30 mL of anhydrous tetrahydrofuran, cesium carbonate (2.11 g, 6.48 mmol) is added, and the mixture is stirred at room temperature for 30 minutes. , P-nitrobenzyl bromide (466 mg, 2.16 mmol) is added and allowed to react for another 16 hours. Next, it is filtered, and the filtrate is concentrated and separated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain a yellow solid (295 mg, yield 38.2%).

5. Preparation of ethyl 2- [1- (4-aminobenzyl) -5-fluoro-1H-indazol-3-yl] acetate
Dissolve ethyl 2- [5-fluoro-1- (4-nitrobenzyl) -1H-indazol-3-yl] acetate (137 mg, 0.383 mmol) in 20 mL of methanol, add 10 mg of 10% Pd / C, and add nitrogen. Incubate for 30 minutes. After detecting the absence of raw materials with TLC (petroleum ether: ethyl acetate = 2: 1), the solid is removed by filtration. The solvent is rotoevaporated to dryness and the resulting solid is used directly in the next reaction.

6. Preparation of ethyl 2- [1- [4- (2-naphthamido) benzyl] -5-fluoro-1H-indazol-3-yl] acetate The crude product obtained above (about 0.383 mmol) and triethylamine ( 1.4 mL) is dissolved in 15 mL of dichloromethane, and 10 mL of dichloromethane solution of 2-naphthoyl chloride (72 mg, 0.38 mmol) is slowly added dropwise in an ice bath, followed by reaction at room temperature for 16 hours. Aqueous sodium bicarbonate is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium and filtered. The filtrate is concentrated under reduced pressure and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (100 mg, total yield of two-stage reaction 54.3%).

7. Preparation of 2- [1- [4- (2-naphthamido) benzyl] -5-fluoro-1H-indazol-3-yl] acetic acid
2- [1- [4- (2-naphthamido) benzyl] -5-fluoro-1H-indazol-3-yl] ethyl acetate (100 mg, 0.208 mmol) is dissolved in 10 mL of tetrahydrofuran, and lithium hydroxide monohydrate in an ice bath After adding 10 mL of an aqueous solution in which the Japanese product (44 mg, 1.05 mmol) is dissolved, the mixture is reacted at room temperature for 3 hours. After detecting the end of the reaction with TLC, water is added, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (90 mg, 95.7% yield).
LC-MS (M + H): 453.7
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.43 (s, 1H), 8.52 (s, 1H), 8.10-7.93 (m, 4H), 7.75-7.67 (m, 3H), 7.66-7.56 ( m, 2H), 7.49 (d, 1H), 7.32-7.21 (m, 3H), 5.57 (s, 2H), 3.90 (s, 2H).

Example 12 Preparation of 2- [1- [4- (2-naphthamido) benzyl] -6-fluoro-1H-indazol-3-yl] acetic acid (Compound 12)

1. Preparation of 3-amino-3- (4-fluoro-2-nitrophenyl) propionic acid
After stirring 4-fluoro-2-nitrobenzaldehyde (16.91 g, 0.10 mol), formic acid (15.2 mL, 0.40 mol) and malonic acid (13.52 g, 0.13 mol) at 45 ° C. for 30 minutes, ammonium formate (15.76 g, Add 0.25mol), warm to 70 ° C and stir for 1 hour. After further stirring at 95 ° C for 4 hours, 38 mL of concentrated hydrochloric acid is added, and the mixture is stirred for 1 hour while maintaining the temperature. Cool, add 20 mL of water, extract twice with ethyl acetate (25 mL × 2) and discard the organic phase. The aqueous phase is adjusted to a pH of about 4.2 with 50% potassium hydroxide solution to precipitate a solid. Suction filtered and vacuum dried to give a yellow solid (16.71 g, 73.2% yield).

2. Preparation of 2- (6-fluoro-1H-indazol-3-yl) acetic acid
3-Amino-3- (4-fluoro-2-nitrophenyl) propionic acid (16.71 g, 73.2 mmol) is dissolved in a mixture of 80 mL of 5% sodium hydroxide solution and 5 mL of 85% hydrazine hydrate and heated to 80 ° C. Heat, add Raney nickel (25mg × 2), react for 30 minutes, cool, adjust the pH to about 2 with 6N hydrochloric acid, and precipitate a solid. Suction filtered and vacuum dried to give a yellow solid (4.63 g, 32.5% yield).

3. Preparation of ethyl 2- (6-fluoro-1H-indazol-3-yl) acetate
2- (6-Fluoro-1H-indazol-3-yl) acetic acid (4.63 g, 23.8 mmol) is dissolved in 60 mL of absolute ethanol and 2.0 mL of concentrated sulfuric acid and heated to reflux for 16 hours. Concentrate under reduced pressure to remove most of the ethanol, add 20 mL of water, and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated to give the product (2.08 g, 39.3% yield).

4. Preparation of ethyl 2- [6-fluoro-1- (4-nitrobenzyl) -1H-indazol-3-yl] acetate
2- (6-Fluoro-1H-indazol-3-yl) ethyl acetate (2.08 g, 9.36 mmol) is dissolved in 30 mL of anhydrous tetrahydrofuran, cesium carbonate (9.15 g, 28.1 mmol) is added, and the mixture is stirred at room temperature for 30 minutes. , P-nitrobenzyl bromide (2.02 g, 9.35 mmol) is added and allowed to react for 16 hours. Filter, concentrate the filtrate, and fractionate on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a yellow solid (1.38 g, 41.2% yield).

5. Preparation of ethyl 2- [1- (4-aminobenzyl) -6-fluoro-1H-indazol-3-yl] acetate
Dissolve ethyl 2- [6-fluoro-1- (4-nitrobenzyl) -1H-indazol-3-yl] acetate (357 mg, 1.0 mmol) in 20 mL of methanol, add 15 mg of 10% Pd / C, and in a nitrogen atmosphere Incubate for 30 minutes. After detecting the absence of the raw material with TLC (petroleum ether: ethyl acetate = 2: 1), the solid is removed by filtration. The solvent is rotoevaporated to dryness and the resulting solid is used directly in the next reaction.

6. Preparation of 2- [1- [4- (2-naphthamido) benzyl] -6-fluoro-1H-indazol-3-yl] ethyl acetate The crude product obtained above, 2- [1- ( 4-Aminobenzyl) -6-fluoro-1H-indazol-3-yl] ethyl acetate (approx. 1.0 mmol) and triethylamine 0.5 mL are dissolved in dichloromethane 15 mL, and slowly 2-naphthoyl chloride (191 mg, 1.0 mmol) in an ice bath After dropwise addition of 10 mL of a dichloromethane solution, the mixture is allowed to react at room temperature for 16 hours. Quench with sodium bicarbonate solution and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. Separation with a silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain a white solid (205 mg, yield 42.6%).

7. Preparation of 2- [1- [4- (2-naphthamido) benzyl] -6-fluoro-1H-indazol-3-yl] acetic acid
2- [1- [4- (2-naphthamido) benzyl] -6-fluoro-1H-indazol-3-yl] ethyl acetate (205 mg, 0.426 mmol) is dissolved in 15 mL of tetrahydrofuran, and lithium hydroxide monohydrate in an ice bath 10 mL of an aqueous solution in which the Japanese product (54 mg, 1.29 mmol) is dissolved is added and reacted at room temperature for 3 hours. After detecting the end of the reaction with TLC, water is added, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (165 mg, 85.4% yield).
LC-MS (M + H): 454.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.43 (s, 1H), 8.54 (s, 1H), 8.09-7.95 (m, 4H), 7.78-7.71 (m, 3H), 7.67-7.54 ( m, 3H), 7.26 (d, 2H), 7.00 (t, 1H), 5.53 (s, 2H), 3.91 (s, 2H).

Example 13 Preparation of 2- [1- [4- (6-Fluoro-2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 13)

1. Preparation of ethyl 2- [1- (4-nitrobenzyl) -1H-indazol-3-yl] acetate
2- (1H-indazol-3-yl) ethyl acetate (9.78 g, 47.9 mmol) is dissolved in 100 mL of anhydrous tetrahydrofuran, cesium carbonate (46.81 g, 143.7 mmol) is added, and the mixture is stirred at room temperature for 30 minutes. Benzyl bromide (10.36 g, 47.96 mmol) is added and allowed to react for 16 hours. Filter and concentrate the filtrate. Separation with a silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain a yellow solid (12.68 g, yield 78.1%).

2. Preparation of ethyl 2- [1- (4-aminobenzyl) -1H-indazol-3-yl] acetate
2- [1- (4-Nitrobenzyl) -1H-indazol-3-yl] ethyl acetate (340 mg, 1.0 mmol) is dissolved in 20 mL of methanol, 10% Pd / C (20 mg) is added, and 30% in a nitrogen atmosphere. The reaction is allowed to proceed for a minute, and after TLC (petroleum ether: ethyl acetate = 2: 1) detects the absence of the raw material, the solid is removed by filtration. The solvent is rotoevaporated to dryness and the resulting solid is used directly in the next reaction.

3. Preparation of ethyl 2- [1- [4- (6-fluoro-2-naphthamido) benzyl] -1H-indazol-3-yl] acetate
6-Fluoro-2-naphthoic acid (228 mg, 1.2 mmol) is dissolved in 15 mL of dichloromethane and 0.1 mL of N, N-dimethylformamide, and oxalyl chloride (228 mg, 1.8 mmol) is slowly added dropwise in an ice bath. Let react for 3 hours at room temperature. Concentrate under reduced pressure to obtain white solid 6-fluoro-2-naphthoyl chloride.

  The crude product of ethyl 2- [1- (4-aminobenzyl) -1H-indazol-3-yl] acetate obtained above (about 1.0 mmol) and 1.4 mL of triethylamine are dissolved in 15 mL of dichloromethane, and the mixture is dissolved in an ice bath. -A 15 mL solution of fluoro-2-naphthoyl chloride (about 1.2 mmol) in dichloromethane is slowly added dropwise, followed by reaction at room temperature for 16 hours, quenching with a sodium bicarbonate solution, and extraction with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate was freed from the solvent under reduced pressure, and the residue was fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (262 mg, total yield of the two-step reaction is 54.4% ).

4. Preparation of 2- [1- [4- (6-Fluoro-2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid
2- [1- [4- (6-Fluoro-2-naphthamido) benzyl] -1H-indazol-3-yl] ethyl acetate (262 mg, 0.544 mmol) is dissolved in 10 mL of tetrahydrofuran, and lithium hydroxide monohydrate in an ice bath 10 mL of an aqueous solution in which the Japanese product (114 mg, 2.71 mmol) is dissolved is added and reacted at room temperature for 3 hours. The end of the reaction is detected by TLC, water is added to the reaction solution, and the pH is adjusted to 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (228 mg, 92.5% yield).
LC-MS (M + H): 453.8
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.43 (s, 1H), 8.55 (s, 1H), 8.15 (dd, 1H), 8.01 (s, 2H), 7.78 (d, 1H), 7.74 -7.67 (m, 3H), 7.64 (d, 1H), 7.51 (t, 1H), 7.37 (t, 1H), 7.24 (d, 2H), 7.12 (t, 1H), 5.56 (s, 2H), 3.91 (s, 2H).

Example 14 Preparation of 2- [1- (4- (2,4-difluorobenzamido) benzyl) -6-fluoro-1H-indazol-3-yl] acetic acid (Compound 14)

1. Preparation of ethyl 2- [1- (4-aminobenzyl) -6-fluoro-1H-indazol-3-yl] acetate
2- [6-Fluoro-1- (4-nitrobenzyl) -1H-indazol-3-yl] ethyl acetate (357 mg, 1.0 mmol) is dissolved in 20 mL of methanol, 10% Pd / C (15 mg) is added, and nitrogen is added. The reaction is carried out in the atmosphere for 30 minutes, and TLC (petroleum ether: ethyl acetate = 2: 1) detects that the raw material is gone, and the solid is removed by filtration. The solvent is rotoevaporated to dryness and the resulting solid is used directly in the next reaction.

2. Preparation of 2- [1- [4- (2,4-difluorobenzamido) benzyl] -6-fluoro-1H-indazol-3-yl] ethyl acetate The crude product obtained above, 2- [ 1- (4-Aminobenzyl) -6-fluoro-1H-indazol-3-yl] ethyl acetate (approximately 1.0 mmol) and triethylamine 0.5 mL were dissolved in 15 mL of dichloromethane, and 2,4-difluorobenzoyl chloride (177 mg) was dissolved in an ice bath. , 1.0 mmol) in dichloromethane is slowly added dropwise, followed by reaction at room temperature for 16 hours. A sodium hydrogen carbonate solution is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (213 mg, combined yield 45.6%).

3. Preparation of 2- [1- [4- (2,4-difluorobenzamido) benzyl] -6-fluoro-1H-indazol-3-yl] acetic acid
2- [1- [4- (2,4-Difluorobenzamido) benzyl] -6-fluoro-1H-indazol-3-yl] ethyl acetate (213 mg, 0.456 mmol) is dissolved in 15 mL of tetrahydrofuran and hydroxylated in an ice bath. 10 mL of an aqueous solution in which lithium monohydrate (58 mg, 1.38 mmol) is dissolved is added and reacted at room temperature for 3 hours. The end of the reaction is detected by TLC, water is added to the reaction solution, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (180 mg, 89.9% yield).
LC-MS (M + H): 440.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.44 (s, 1H), 7.77-7.66 (m, 2H), 7.62 (d, 2H), 7.55 (dd, 1H), 7.38 (td, 1H) , 7.23 (d, 2H), 7.19 (1H, td), 6.99 (td, 1H), 5.51 (s, 2H), 3.90 (s, 2H).

Example 15 Preparation of 2- [1-[[6- (2-naphthamido) pyridin-3-yl] methyl] -1H-indazol-3-yl] acetic acid (Compound 15)

1. Preparation of N- (2-naphthylformyl) -N- (5-methylpyridin-2-yl) -2-naphthamide
Dissolve 5-methylpyridin-2-amine (1.08 g, 10.0 mmol) and triethylamine (2.02 g, 20.0 mmol) in 50 mL of dichloromethane and add 10 mL of dichloromethane solution of 2-naphthoyl chloride (1.90 g, 10.0 mmol) in an ice bath. Slowly add and react at room temperature for 16 hours. Aqueous sodium bicarbonate is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. Concentrate under reduced pressure to obtain a white solid (2.91 g, yield 69.9%).

2. Preparation of N- (5-methylpyridin-2-yl) -2-naphthamide
N- (2-naphthylformyl) -N- (5-methylpyridin-2-yl) -2-naphthamide (2.91 g, 6.99 mmol) is dissolved in a mixture of ethanol (50 mL) and 85% hydrazine hydrate (5 mL) at room temperature. For 8 hours. Concentrate under reduced pressure and fractionate with a silica gel column (petroleum ether: ethyl acetate = 3: 1) to obtain a white solid (1.8 g, yield 98.1%).

3. Preparation of N- [5- (bromomethyl) pyridin-2-yl] -2-naphthamide
Carbon tetrachloride containing N- (5-methylpyridin-2-yl) -2-naphthamide (1.31 g, 5.0 mmol), N-bromosuccinimide (0.89 g, 5.0 mmol) and dibenzoyl peroxide (0.12 g, 0.5 mmol) Dissolve in 50 mL and allow to react for 16 hours in a nitrogen atmosphere. Filter while the reaction is warm and wash the solid with carbon tetrachloride. The filtrate is concentrated and fractionated on a silica gel column (petroleum ether: ethyl acetate = 5: 1) to obtain a white solid (0.66 g, yield 38.6%).

4. Preparation of 2- [1-[[6- (2-naphthamidono) pyridin-3-yl] methyl] -1H-indazol-3-yl] ethyl acetate
2- (1H-indazol-3-yl) ethyl acetate (320 mg, 1.57 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran, cesium carbonate (1.53 g, 4.70 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and then N- [5 -(Bromomethyl) pyridin-2-yl] -2-naphthamide (532 mg, 1.56 mmol) is added and allowed to react for 16 hours. The solid is filtered and the filtrate is concentrated and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a pale yellow solid (154 mg, 21.2% yield).

5. Preparation of 2- [1-[[6- (2-naphthamido) pyridin-3-yl] methyl] -1H-indazol-3-yl] acetic acid
2- [1-[[6- (2-naphthamido) pyridin-3-yl] methyl] -1H-indazol-3-yl] ethyl acetate (154 mg, 0.33 mmol) is dissolved in 20 mL of tetrahydrofuran and hydroxylated in an ice bath. Add 10 mL of an aqueous solution of lithium monohydrate (70 mg, 1.67 mmol) and react at room temperature for 3 hours. The end of the reaction is detected by TLC. Water is added to the reaction solution, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (69 mg, 47.7% yield).
LC-MS (M + H): 437.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.99 (s, 1H), 8.66 (s, 1H), 8.38 (s, 1H), 8.14 (d, 1H), 8.10-7.95 (m, 4H) , 7.80-7.69 (m, 3H), 7.68-7.56 (m, 2H), 7.45-7.35 (m, 1H), 7.18-7.09 (m, 1H), 5.64 (s, 2H), 3.92 (s, 2H) .

Example 16 Preparation of 2- [1- [4- (4-cyanobenzamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 16)

1. Preparation of ethyl 2- [1- [4- (4-cyanobenzamido) benzyl] -1H-indazol-3-yl] acetate
2- [1- (4-Aminobenzyl) -1H-indazol-3-yl] ethyl acetate (176 mg, 0.569 mmol) and triethylamine (173 mg, 1.71 mmol) are dissolved in 15 mL of dichloromethane and 4-cyanobenzoyl chloride is dissolved in an ice bath. After slowly adding dropwise 10 mL of a solution of (95 mg, 0.574 mmol) in dichloromethane, the mixture is allowed to react at room temperature for 16 hours. Quench with sodium bicarbonate solution and extract with ethyl acetate. The organic phase is dried and filtered with anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. Separation with a silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain a white solid (121 mg, yield 48.5%).

2. Preparation of 2- [1- [4- (4-Cyanobenzamido) benzyl] -1H-indazol-3-yl] acetic acid
2- [1- [4- (4-Cyanobenzamido) benzyl] -1H-indazol-3-yl] ethyl acetate (121 mg, 0.276 mmol) is dissolved in 20 mL of tetrahydrofuran, and lithium hydroxide monohydrate ( 58 mL, 1.38 mmol) of aqueous solution is added, and the mixture is allowed to react at room temperature for 3 hours. The end of the reaction is detected by TLC, water is added to the reaction solution, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter, dry and recrystallize with ethyl acetate to give a white solid (69 mg, 60.9% yield).
LC-MS (M + H): 411.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.47 (s, 1H), 8..04 (d, 2H), 7.98 (d, 2H), 7.75-7.60 (m, 4H), 7.36 (t , 1H), 7.23 (d, 2H), 7.11 (t, 1H), 5.55 (s, 2H), 3.91 (s, 2H).

Example 17 Preparation of 2- [1- [4- (6-methylnicotinamide) benzyl] -1H-indazol-3-yl] acetic acid (Compound 17)

1. Preparation of ethyl 2- [1- [4- (6-methylnicotinamide) benzyl] -1H-indazol-3-yl] acetate
6-Methylnicotinic acid (138 mg, 1.00 mmol) is dissolved in a mixture of 15 mL of dichloromethane and 0.10 mL of N, N-dimethylformamide, and oxalyl chloride (192 mg, 1.51 mmol) is slowly added dropwise in an ice bath. Let react for hours. Concentrate under reduced pressure to obtain 6-methylnicotinoyl chloride as a white solid.
2- [1- (4-aminobenzyl) -1H-indazol-3-yl] ethyl acetate (258 mg, 0.83 mmol) and triethylamine (0.4 mL, 2.87 mmol) were dissolved in 15 mL of dichloromethane and prepared in an ice bath. After slowly adding dropwise 10 mL of a solution of methylnicotinoyl chloride (about 1.0 mmol) in dichloromethane, the mixture is allowed to react at room temperature for 16 hours. Quench the reaction by adding sodium hydrogen carbonate solution and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (258 mg, yield 72.3%).

2. Preparation of 2- [1- [4- (6-Methylnicotinamide) benzyl] -1H-indazol-3-yl] acetic acid
2- [1- [4- (6-Methylnicotinamide) benzyl] -1H-indazol-3-yl] ethyl acetate (258 mg, 0.60 mmol) is dissolved in 20 mL of tetrahydrofuran and lithium hydroxide monohydrate in an ice bath. 10 mL of an aqueous solution (76 mg, 1.81 mmol) is added and allowed to react at room temperature for 3 hours. After detecting the end of the reaction with TLC, water is added to the reaction solution, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (230 mg, 95.4% yield).
LC-MS (M + H): 401.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.46 (s, 1H), 8.97 (d, 1H), 8.21 (dd, 1H), 7.73-7.66 (m, 3H), 7.64 (d, 1H) , 7.39 (d, 1H), 7.34 (d, 1H), 7.21 (d, 2H), 7.10 (t, 1H), 5.55 (s, 2H), 3.91 (s, 2H), 2.52 (s, 3H).

Example 18 Preparation of 2- [1- [4- (1-methyl-1H-pyrazole-4-carboxamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 18)

1. Preparation of ethyl 2- [1- [4- (1-methyl-1H-pyrazol-4-carboxamido) benzyl] -1H-indazol-3-yl] acetate
1-Methyl-1H-pyrazole-4-formic acid (151 mg, 1.20 mmol) is dissolved in a mixture of 15 mL of dichloromethane and 0.10 mL of N, N-dimethylformamide, and oxalyl chloride (229 mg, 1.80 mmol) is slowly added dropwise in an ice bath. And allowed to react at room temperature for 3 hours. Concentration under reduced pressure gives 1-methyl-1H-pyrazole-4-formyl chloride as a white solid.
2- [1- (4-aminobenzyl) -1H-indazol-3-yl] ethyl acetate (309 mg, 1.00 mmol) and triethylamine (0.41 mL, 2.9 mmol) were dissolved in 15 mL of dichloromethane and prepared in an ice bath. 10 mL of a dichloromethane solution of methyl-1H-pyrazole-4-formyl chloride (about 1.20 mmol) is slowly added dropwise, followed by reaction at room temperature for 16 hours. Quench the reaction by adding aqueous sodium bicarbonate and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (279 mg, 67% yield).

2. Preparation of 2- [1- [4- (1-Methyl-1H-pyrazol-4-carboxamido) benzyl] -1H-indazol-3-yl] acetic acid
2- [1-4- (1-Methyl-1H-pyrazole-4-carboxamido) benzyl] -1H-indazol-3-yl] ethyl acetate (279 mg, 0.67 mmol) is dissolved in 20 mL of tetrahydrofuran and water is added in an ice bath. Add 10 mL of an aqueous solution of lithium oxide monohydrate (84 mg, 2.0 mmol) and allow to react at room temperature for 3 hours. The end of the reaction is detected by TLC, water is added to the reaction solution, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (246 mg, 94.5% yield).
LC-MS (M + H): 390.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 12.96-12.05 (br s, 1H), 9.78 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.70 (d, 1H ), 7.67-7.56 (m, 3H), 7.35 (t, 1H), 7.19 (d, 2H), 7.10 (t, 1H), 5.53 (s, 2H), 3.91 (s, 2H), 3.86 (s, 3H).

Example 19 Preparation of 2- (1-((5- (2-naphthamido) pyrazin-2-yl) methyl) -1H-indazol-3-yl) acetic acid (Compound 19)

1. Preparation of tert-butyl 5-methylpyrazin-2-ylcarbamate
5-methylpyrazine-2-formic acid (13.81 g, 0.1 mol), tert-butyl alcohol (95 mL, 1 mol), triethylamine (27.9 mL, 0.2 mol) and diphenylphosphoric acid azide (30.27 g, 0.11 mol) in 300 mL of toluene Dissolve, warm to reflux and react for 8 hours. Separation with a silica gel column (petroleum ether: ethyl acetate = 20: 1) to obtain a pale yellow solid (15.2 g, yield 72.7%).

2. Preparation of 5-methylpyrazin-2-amine
Dissolve tert-butyl 5-methylpyrazin-2-ylcarbamate (6.27 g, 30.0 mmol) in 30 mL of dichloromethane, slowly add 20 mL of trifluoroacetic acid in an ice bath, move to room temperature, and react for 1 hour. The solvent is rotoevaporated to dryness and the resulting solid is used directly in the next reaction.

3. Preparation of N- (2-naphthylformyl) -N- (5-methylpyrazin-2-yl) -2-naphthamide To the above reaction system, add 100 mL of dichloromethane and triethylamine (12.5 mL, 0.09 mol) and ice bath Then slowly add 30 mL of 2-naphthoyl chloride (5.72 g, 30.0 mmol) in dichloromethane and allow to react in an ice bath for 2 hours. The solvent is rotoevaporated to dryness and the resulting solid is used directly in the next reaction.

4. Preparation of N- (5-methylpyrazin-2-yl) -2-naphthamide 100 mL of absolute ethanol is added to the above reaction system, and 15 mL of 85% hydrazine hydrate is added dropwise and reacted at room temperature for 12 hours. The solvent is rotoevaporated to dryness and fractionated on a silica gel column (petroleum ether: ethyl acetate = 3: 1) to give a white solid (4.1 g, total yield of 3 steps reaction is 51.9%).

5. Preparation of N- [5- (bromomethyl) pyrazin-2-yl] -2-naphthamide
N- (5-methylpyrazin-2-yl) -2-naphthamide (2.63 g, 10.0 mmol) is dissolved in 30 mL of carbon tetrachloride, NBS (1.96 g, 11.0 mmol), BPO (242 mg, 1.0 mmol) are added, The temperature is raised to reflux and the reaction is allowed to proceed for 12 hours in the dark. The solvent is rotoevaporated to dryness and the resulting solid is used directly in the next reaction.

6. Preparation of ethyl 2- [1-[[5- (2-naphthamido) pyrazin-2-yl] methyl] -1H-indazol-3-yl] ethyl acetate Compound (1H-indazol-3-yl) ethyl acetate ( 1.84 g, 9.0 mmol) is dissolved in 10 mL of DMA, and sodium hydride (60%, 0.44 g, 11 mmol) is added in several portions in an ice bath and allowed to react at room temperature for 1 hour. Next, all the products obtained by the above reaction are added, and the mixture is allowed to react at room temperature for 12 hours with shading. Quench the reaction by adding water, extract three times with ethyl acetate, wash the organic phase twice with saturated brine, dry and concentrate. Separation with a silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain a yellow solid (0.5 g, yield 11.9%).

7. Preparation of 2- [1-[[5- (2-naphthamido) pyrazin-2-yl] methyl] -1H-indazol-3-yl] acetic acid
2- [1-[[5- (2-naphthamido) pyrazin-2-yl] methyl] -1H-indazol-3-yl] ethyl acetate (0.466 g, 1.0 mmol) was dissolved in 20 mL of tetrahydrofuran, 10 mL of an aqueous solution in which lithium hydroxide monohydrate (0.18 g, 4.3 mmol) is dissolved is added and allowed to react for 3 hours. The solvent is rotoevaporated to dryness and purified by preparative chromatography (methanol: water = 50%) to give a white solid (130 mg, 29.7% yield).
LC-MS (M + H): 438.2
¹ H-NMR (d ₆ -DMSO, 400 MHz): d 12.90 (1H, s), 11.35 (1H, s), 9.43 (1H, d), 8.74 (1H, s), 8.46 (1H, s), 8.12-8.02 (3H, m), 8.05-7.99 (1H, m), 7.72 (1H, d), 7.69-7.60 (2H, m), 7.49 (1H, d), 7.33 (1H, t), 7.09 ( 1H, t), 5.27 (2H, s), 4.14 (2H, s).

Example 20 2- [1- [4- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-carboxamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 20) Production

1. Preparation of ethyl 2- [1- [4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-carboxamido) benzyl] -1H-indazol-3-yl] acetate
Dissolve 2,3-dihydrobenzo [b] [1,4] dioxin-6-formic acid (154 mg, 0.85 mmol) in a mixture of 15 mL dichloromethane and N, N-dimethylformamide (0.10 mL) and oxalyl chloride in an ice bath (162 mg, 1.28 mmol) is slowly added dropwise, followed by reaction at room temperature for 3 hours. Concentration under reduced pressure gives 2,3-dihydrobenzo [b] [1,4] dioxin-6-benzoyl chloride as a white solid.
2- [1- (4-aminobenzyl) -1H-indazol-3-yl] ethyl acetate (175 mg, 0.566 mmol) and triethylamine (0.22 mL, 1.58 mmol) were dissolved in 15 mL of dichloromethane and prepared in an ice bath 2 10 mL of a dichloromethane solution of 1,3-dihydrobenzo [b] [1,4] dioxin-6-benzoyl chloride (about 0.85 mmol) is slowly added dropwise, followed by reaction at room temperature for 16 hours. A sodium hydrogen carbonate solution is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (260 mg, yield 97.3%).

2. Preparation of 2- [1- [4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-carboxamido) benzyl-1H-indazol-3-yl] acetic acid
2- [1- [4- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-carboxamido) benzyl] -1H-indazol-3-yl] ethyl acetate (260 mg, 0.551 mmol) Dissolve in 20 mL of tetrahydrofuran, add 10 mL of an aqueous solution of lithium hydroxide monohydrate (70 mg, 1.67 mmol) in an ice bath, and react at room temperature for 3 hours. The end of the reaction is detected by TLC, water is added to the reaction system, and the pH is adjusted to 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filtration and drying gives a white solid (241 mg, 98.5% yield).
LC-MS (M + H): 444.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 10.05 (s, 1H), 7.70 (d, 1H), 7.68-7.60 (m, 3H), 7.49-7.42 (m, 2H), 7.35 (t, 1H), 7.19 (d, 2H), 7.10 (t, 1H), 6.94 (d, 1H), 5.54 (s, 2H), 4.30-4.24 (m, 4H), 3.91 (s, 2H).

Example 21 of 2- [1- [4- (2,3-Dihydrobenzo [b] [1,4] dioxin-2-carboxamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 21) Production

1. Preparation of ethyl 2- [1- [4- (2,3-dihydrobenzo [b] [1,4] dioxin-2-carboxamido) benzyl] -1H-indazol-3-yl] acetate
Dissolve 2,3-dihydrobenzo [b] [1,4] dioxin-2-formic acid (145 mg, 0.80 mmol) in a mixture of 15 mL dichloromethane and 0.10 mL N, N-dimethylformamide and oxalyl chloride (153 mg in an ice bath) , 1.21 mmol) is slowly added dropwise and allowed to react at room temperature for 3 hours. Concentration under reduced pressure gives 2,3-dihydrobenzo [b] [1,4] dioxin-2-benzoyl chloride as a white solid.
2- [1- (4-aminobenzyl) -1H-indazol-3-yl] ethyl acetate (165 mg, 0.533 mmol) and triethylamine (0.22 mL, 1.58 mmol) were dissolved in 15 mL of dichloromethane and prepared in an ice bath 2 , 3-Dihydrobenzo [b] [1,4] dioxin-2-benzoyl chloride (about 0.80 mmol) in 10 mL of dichloromethane is slowly added dropwise, followed by reaction at room temperature for 16 hours. Aqueous sodium bicarbonate is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure and fractionated on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to give a white solid (160 mg, yield 63.6%).

2. Preparation of 2- [1- [4- (2,3-dihydrobenzo [b] [1,4] dioxin-2-carboxamido) benzyl] -1H-indazol-3-yl] acetic acid
2- [1- [4- (2,3-Dihydrobenzo [b] [1,4] dioxin-2-carboxamido) benzyl] -1H-indazol-3-yl] ethyl acetate (160 mg, 0.339 mmol) Dissolve in 20 mL of tetrahydrofuran, add 10 mL of aqueous lithium hydroxide monohydrate (43 mg, 1.02 mmol) in an ice bath, and allow to react at room temperature for 3 hours. The end of the reaction is detected by TLC, water is added to the reaction system, and the pH is adjusted to about 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter and dry to give a white solid (145 mg, 96.5% yield).
LC-MS (M + H): 444.2
¹ H NMR (d ₆ -DMSO, 400 MHz) δ: 12.67-12.25 (1H, br s), 10.11 (s, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.53 (d, 2H ), 7.35 (t, 1H), 7.19 (d, 2H), 7.10 (t, 1H), 7.00 (d, 1H), 6.90-6.79 (m, 3H), 5.53 (s, 2H), 4.92 (dd, 1H), 4.40 (dd, 1H), 4.29 (dd, 1H), 3.90 (s, 2H).

Example 22 Preparation of 2- [1- [4- (N-methyl-2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid (Compound 22)

1. Preparation of methyl 2- [1- [4- (N-methyl-2-naphthamido) benzyl] -1H-indazol-3-yl] acetate
2- [1- [4- (2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid (435 mg, 1.0 mmol) is dissolved in 30 mL of anhydrous tetrahydrofuran and 60% sodium hydride (200 mg, 5.0 mmol) is dissolved. After stirring for 30 minutes in an ice bath, methane iodide (284 mg, 2.0 mmol) is added and allowed to react in an ice bath for 3 hours. The reaction solution is slowly put into ice water, extracted with dichloromethane, and the organic phase is dried over anhydrous sodium sulfate. Filter and concentrate, and use the resulting solid directly in the next reaction.

2. Preparation of 2- [1- [4- (N-methyl-2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid
2- [1- [4- (N-methyl-2-naphthamido) benzyl] -1H-indazol-3-yl] acetic acid methyl (approximately 1.0 mmol) is dissolved in 30 mL of tetrahydrofuran, and lithium hydroxide monohydrate in an ice bath. 20 mL of an aqueous solution in which a Japanese product (210 mg, 5.0 mmol) is dissolved is added and reacted at room temperature for 3 hours. The end of the reaction is detected by TLC, water is added to the reaction solution, and the pH is adjusted to 3 to 4 with dilute hydrochloric acid to precipitate a solid. Filter, dry and purify by preparative chromatography to obtain a white solid (147 mg, total yield of two-step reaction is 32.7%).
LC-MS (M + H): 450.2
¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.84 (s, 1H), 7.74 (d, 1H), 7.70-7.65 (m, 2H), 7.57 (d, 1H), 7.52-7.40 (m, 2H) , 7.33-7.27 (m, 2H), 7.19-7.13 (m, 2H), 7.04-6.98 (m 4H), 5.45 (s, 2H), 4.07 (s, 2H), 3.50 (s, 3H).

Example 23 Preparation of 2- [1- [4- (2-naphthamido) benzyl] -1H-pyrazolo [3,4-b] pyridin-3-yl] acetic acid (Compound 23)

1. Preparation of 3-methyl-1H-pyrazolo [3,4-b] pyridine-1-formate-tert-butyl
3-Methyl-1H-pyrazolo [3,4-b] pyridine (4.0 g, 30.0 mmol), triethylamine (6.0 g, 59.3 mmol) and DMAP (366 mg, 3.0 mmol) are placed in 200 mL of dichloromethane and dicarbonated in an ice bath. Di-tert-butyl (6.55 g, 30 mmol) is added dropwise, then transferred to room temperature and reacted for another 12 hours. After completion of the reaction, it was washed twice with 100 mL of 2M aqueous sodium dihydrogen phosphate solution and once with 100 mL of saturated brine, and then the organic phase was dried over anhydrous sodium sulfate and rotoevaporated to obtain a yellow oil. (6.8 g, 97% yield).

2. Preparation of 3- (bromomethyl) -1H-pyrazolo [3,4-b] pyridine-1-formate-tert-butyl
3-methyl-1H-pyrazolo [3,4-b] pyridine-1-formate-tert-butyl (6.6 g, 28.3 mmol) was added to 300 mL of trifluorotoluene, heated to 75 ° C., and then NBS (5.04 g, 28.3 mmol). 15 minutes later, AIBN (465 mg, 2.8 mmol) is added, and the mixture is heated to 80 ° C. and allowed to react for 1 hour. Cool slowly to room temperature and react for another 12 hours. Filter to remove solids. The filtrate is rotoevaporated and fractionated on a column (PE: EA = 25: 1) to give a white solid (730 mg, yield 8.3%).

3. Preparation of 3- (cyanomethyl) -1H-pyrazolo [3,4-b] pyridine-1-formate-tert-butyl
3- (Bromomethyl) -1H-pyrazolo [3,4-b] pyridine-1-formate-tert-butyl (700 mg, 2.24 mmol), potassium carbonate (370 mg, 2.68 mmol) and TMSCN (265 mg, 2.67 mmol) in acetonitrile Add to 10 mL, heat to 60 ° C., and react for 9 hours. After the reaction is complete, cool, add 100 mL of 1M sodium hydroxide solution, and extract with 150 mL of ethyl acetate. The organic phase is washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin to dryness and fractionate on a column (PE: EA = 20: 1) to give a white solid (460 mg, 79.5% yield).

4. Preparation of 2- (1H-pyrazolo [3,4-b] pyridin-3-yl) acetic acid
3- (Cyanomethyl) -1H-pyrazolo [3,4-b] pyridine-1-formate-tert-butyl (460 mg, 1.78 mmol) is added to 10 mL of concentrated hydrochloric acid, and the mixture is heated to 100 ° C. and reacted for 30 minutes. The end of the reaction is detected by LC-MS. The solvent is rotoevaporated to dryness to give a crude product (317 mg) as a white solid.

5. Preparation of methyl 2- (1H-pyrazolo [3,4-b] pyridin-3-yl) acetate
2- (1H-pyrazolo [3,4-b] pyridin-3-yl) acetic acid (317 mg, crude product) was dissolved in 15 mL of methanol, 0.5 mL of concentrated sulfuric acid was added dropwise, and the temperature was raised to 70 ° C. Let react for hours. Detect the completion of the reaction with LC-MS, add 50 mL of water, adjust the pH to be weakly acidic with potassium carbonate, and rotary-evaporate the methanol. Extraction with ethyl acetate, drying over anhydrous sodium sulfate, followed by rotary evaporation to dryness gives a pale yellow solid (250 mg, 73.6% total yield over two steps).

6. Preparation of methyl 2- [1- (4-nitrobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] acetate
Methyl 2- (1H-pyrazolo [3,4-b] pyridin-3-yl) acetate (250 mg, 1.31 mmol) and cesium carbonate (850 mg, 2.61 mmol) were placed in 30 mL of tetrahydrofuran and stirred at room temperature for 15 minutes. -Nitrobenzyl bromide (283 mg, 1.31 mmol) is added and allowed to react for 12 hours at room temperature. Filtration, rotary evaporation of the filtrate, drying and fractionation on a column (PE: EA = 10: 1) gives a pale yellow solid (75 mg, 17.6% yield).

7. Preparation of methyl 2- [1- (4-aminobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] acetate
2- [1- (4-Nitrobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] acetic acid methyl (75 mg, 0.23 mmol) was dissolved in 10 mL of tetrahydrofuran and 10% Pd / C (5 mg ) And react for 2 hours in a nitrogen atmosphere. Filter and rotary evaporate the filtrate to dryness to give a white solid (58 mg, 87% yield).

8. Preparation of methyl 2- [1- [4- (2-naphthamido) benzyl] -1H-pyrazolo [3,4-b] pyridin-3-yl] acetate
2- [1- (4-aminobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] acetic acid methyl (58 mg, 0.20 mmol) and triethylamine (41 mg, 0.41 mmol) are dissolved in 15 mL of dichloromethane, After adding 2-naphthoyl chloride (38 mg, 0.20 mmol) in an ice bath, the mixture is allowed to react at room temperature for an additional hour. The solvent is rotoevaporated to dryness and fractionated on a column (PE: EA = 15: 1) to give a white oil (60 mg, 65% yield).

9. Preparation of 2- [1- [4- (2-naphthamido) benzyl] -1H-pyrazolo [3,4-b] pyridin-3-yl] acetic acid
Methyl 2- [1- [4- (2-naphthamido) benzyl] -1H-pyrazolo [3,4-b] pyridin-3-yl] acetate (60 mg, 0.13 mmol) and lithium hydroxide monohydrate (10 mg , 0.24 mmol) in a mixture of 5 mL of tetrahydrofuran and 20 mL of water and allowed to react at room temperature for 2 hours. Tetrahydrofuran is removed by rotary evaporation, adjusted to pH 3 with 1 mol / L hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase is rotary evaporated to dryness to give a pale brown solid (28 mg, 49.3% yield).
LC-MS (MH): 435.2
¹ H-NMR (d ₆ -DMSO, 400 MHz) d 10.43 (1H, s), 8.56 (1H, dd), 8.51 (1H, s), 8.22 (1H, dd), 8.10-7.98 (4H, m) , 7.70 (2H, d), 7.66-7.55 (2H, m), 7.30-7.21 (3H, m), 5.60 (2H, s), 3.95 (2H, s).

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L1は-(C(R1aR1b))p-であり、pは1、2、3、4または5であり；

が−C＝である場合、R1aとR1bはそれぞれ独立して水素、ハロゲン、ヒドロキシ、C1-6アルキル、ハロゲン化C1-6アルキル、C1-6アルコキシまたはC3-6シクロアルキルであり；ここで、R1aとR1bがそれらに結合しているC原子と、C3-6シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC3-6ヘテロシクロアルキルを形成しても良い；上記のC3-6シクロアルキル及びC3-6ヘテロシクロアルキルは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C1-6アルキル、ハロゲン化C1-6アルキルまたはC1-6アルコキシから選ばれ；

が−N−である場合、R1aとR1bはそれぞれ独立して水素、C1-6アルキル、ハロゲン化C1-6アルキルまたはC3-6シクロアルキルであり；ここで、R1aとR1bがそれらに結合しているC原子と、C3-6シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC3-6ヘテロシクロアルキルを形成しても良い；上記のC3-6シクロアルキル及びC3-6ヘテロシクロアルキルは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C1-6アルキル、ハロゲン化C1-6アルキル、C1-6アルコキシまたはハロゲン化C1-6アルコキシから選ばれ；
WはR2aOC(O)-、(R2a)2NC(O)-またはテトラゾリルであり、
R2aは水素、C1-6アルキルまたはC3-8シクロアルキルであり；
L2は-(C(R3aR3b))p-であり、pは1、2、3、4または5であり；

が−C＝である場合、R3aとR3bはそれぞれ独立して水素、ハロゲン、ヒドロキシ、C1-6アルキルまたはC3-6シクロアルキルであり；ここで、R3aとR3bがそれらに結合しているC原子と、C3-6シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC3-6ヘテロシクロアルキルを形成しても良い；上記のC3-6シクロアルキル及びC3-6ヘテロシクロアルキルは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C1-6アルキル、ハロゲン化C1-6アルキル、C1-6アルコキシまたはC3-8シクロアルキルから選ばれ；

が−N−である場合、R3aとR3bはそれぞれ独立して水素、C1-6アルキル、ハロゲン化C1-6アルキルまたはC3-6シクロアルキルであり；ここで、R3aとR3bがそれらに結合しているC原子と、C3-6シクロアルキルまたはO、NまたはS原子の中の少なくとも1つを含むC3-6ヘテロシクロアルキルを形成しても良い；上記のC3-6シクロアルキル及びC3-6ヘテロシクロアルキルは任意に1、2、3、4、5または6個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C1-6アルキル、ハロゲン化C1-6アルキル、C1-6アルコキシ、C3-8シクロアルキルから選ばれ；
Xはアリール基またはヘテロ環基であり、Xは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してハロゲン、ヒドロキシ、C1-6アルキル、ハロゲン化C1-6アルキル、C1-6アルコキシまたはC3-8シクロアルキルから選ばれ；
L3は-N(R5a)-C(O)-であり、R5aは水素またはC1-6アルキルであり；
YはC3-8シクロアルキル、アリール基または3-10員ヘテロ環基であり、Yは任意に1、2、3、4または5個の置換基に置換されても良い；ここの置換基は、独立してヒドロキシ、ハロゲン、シアノ、C1-6アルキル、ヒドロキシC1-6アルキル、ハロゲン化C1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、ハロゲン化C1-6アルコキシ、C3-8シクロアルキル、C1-6アルキルアミノ、ジ(C1-6アルキル)アミノ、C1-6アルキルチオ、フェニル、フェノキシ、C5-8ヘテロシクロアルキル、C5-8ヘテロシクロアルコキシ、C1-6アルキルカルボニル、C1-6アルキルカルバモイル、ホルムアミド基、C1-6アルキルアミド基、C1-6アルキルアミノスルホニル、C1-6アルキルスルホニルアミノ、ジ(C1-6アルキル)カルバモイルまたはジ(C1-6アルキル)アミノスルホニルから選ばれる。 Where X1, X2, X3 and X4 are each independently N or C (R1), and X5 is N or C (R2);
R1 is hydrogen, cyano, hydroxy, amino, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-8 cycloalkyl C1-6 Alkyl, C2-6 alkenyl, C5-8 cycloalkenyl, C1-6 alkylthio, C1-6 alkylamino, di (C1-6 alkyl) amino, C1-6 alkylcarbamoyl, formamide group, C1-6 alkylamide group, C1 -6 alkylaminosulfonyl, C1-6 alkylsulfonylamino, di (C1-6 alkyl) carbamoyl, di (C1-6 alkyl) aminosulfonyl, C1-6 alkoxycarbonyl or C1-6 alkylcarbonyloxy;
R2 is hydrogen, cyano, amino, nitro, hydroxy, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C3-8 cycloalkyl C1 -6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl C2-6 alkenyl, C5-8 cycloalkenyl, C5-8 cycloalkenyl C1-6 alkyl, C2-6 alkynyl, phenyl, phenyl C1-6 alkyl, naphthyl, C3-8 heterocycloalkyl, C3-8 heterocycloalkyl C1-6 alkyl, C1-6 alkylamino, di (C1-6 alkyl) amino, C1-6 alkylcarbamoyl, formamide group, C1-6 alkylamide group, C1 -6 alkylaminosulfonyl, C1-6 alkylsulfonylamino, di (C1-6 alkyl) carbamoyl or di (C1-6 alkyl) aminosulfonyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L1 is-(C (R1aR1b)) p-, p is 1, 2, 3, 4 or 5;

When R is -C =, each R1a and R1b is independently hydrogen, halogen, hydroxy, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or C3-6 cycloalkyl; R1a and R1b may form a C3-6 cycloalkyl or C3-6 heterocycloalkyl containing at least one of O, N or S atoms with the C atom bonded to them; -6 cycloalkyl and C3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C1-6 Selected from alkyl, halogenated C1-6 alkyl or C1-6 alkoxy;

R1a and R1b are each independently hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, or C3-6 cycloalkyl; where R1a and R1b are attached to them And C3-6 cycloalkyl or C3-6 heterocycloalkyl containing at least one of O, N or S atoms may be formed; and the above C3-6 cycloalkyl and C3-6 hetero Cycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C1-6 alkyl, halogenated C1-6 alkyl, Selected from C1-6 alkoxy or halogenated C1-6 alkoxy;
W is R2aOC (O)-, (R2a) 2NC (O)-or tetrazolyl,
R2a is hydrogen, C1-6 alkyl or C3-8 cycloalkyl;
L2 is-(C (R3aR3b)) p-, p is 1, 2, 3, 4 or 5;

Is —C═, R 3a and R 3b are each independently hydrogen, halogen, hydroxy, C 1-6 alkyl or C 3-6 cycloalkyl; where R 3a and R 3b are attached to them And may form a C3-6 cycloalkyl or a C3-6 heterocycloalkyl containing at least one of the O, N or S atoms; the above C3-6 cycloalkyl and C3-6 heterocycloalkyl are Optionally, 1, 2, 3, 4 or 5 substituents may be substituted; these substituents are independently halogen, hydroxy, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 Selected from alkoxy or C3-8 cycloalkyl;

R3a and R3b are each independently hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, or C3-6 cycloalkyl; where R3a and R3b are attached to them, And C3-6 cycloalkyl or C3-6 heterocycloalkyl containing at least one of O, N or S atoms may be formed; and the above C3-6 cycloalkyl and C3-6 hetero Cycloalkyls may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy, C1-6 alkyl, halogenated C1-6 Selected from alkyl, C1-6 alkoxy, C3-8 cycloalkyl;
X is an aryl group or a heterocyclic group, and X may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C1- Selected from 6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or C3-8 cycloalkyl;
L3 is -N (R5a) -C (O)-, R5a is hydrogen or C1-6 alkyl;
Y is a C3-8 cycloalkyl, aryl group or 3-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2, 3, 4 or 5 substituents; , Independently hydroxy, halogen, cyano, C1-6 alkyl, hydroxy C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, halogenated C1-6 alkoxy, C3 -8 cycloalkyl, C1-6 alkylamino, di (C1-6 alkyl) amino, C1-6 alkylthio, phenyl, phenoxy, C5-8 heterocycloalkyl, C5-8 heterocycloalkoxy, C1-6 alkylcarbonyl, C1 -6 alkylcarbamoyl, formamide group, C1-6 alkylamido group, C1-6 alkylaminosulfonyl, C1-6 alkylsulfonylamino, di (C1-6 alkyl) carbamoyl or di (C1-6 alkyl) aminosulfonyl .

はそれぞれ独立して−N−または−C＝であり、且つ

は同時に―N―であることはない；
L1は-CH2-であり；
Wは-C(O)OHであり；
L2は-CH2-であり；
Xはフェニル、ピリジルまたはピラジニルであり；
L3は-N(R5a)-C(O)-であり、R5aは水素またはメチルであり；
Yはフェニル、ピリジル、ピラゾリル、ナフチルまたは2,3-ジヒドロベンゾ[b][1,4]ジオキサニルであり、Yは任意に1または2個の置換基に置換されても良い；ここの置換基は、独立してフッ素、塩素、臭素、シアノ、メチル、エチル、イソプロピル、tert-ブチルまたはトリフルオロメチルから選ばれる。 Wherein X1, X2, and X3 are each independently C (R1), X4 is N or C (R1), and X5 is N or C (R2);
R1 is hydrogen or fluorine;
R2 is hydrogen or C1-4 alkyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L1 is -CH2-;
W is -C (O) OH;
L2 is -CH2-;
X is phenyl, pyridyl or pyrazinyl;
L3 is -N (R5a) -C (O)-and R5a is hydrogen or methyl;
Y is phenyl, pyridyl, pyrazolyl, naphthyl or 2,3-dihydrobenzo [b] [1,4] dioxanyl, Y may optionally be substituted with 1 or 2 substituents; Are independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl.

In the present specification, “C2-6 alkenyl” means a straight or branched alkenyl having a double bond and having 2 to 6 C atoms. For example, “C2-4 alkenyl”, “C2-5 alkenyl”, “C2-3 alkenyl” and the like are included. Examples thereof are vinyl group, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1- Methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl- 1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3- Butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl -1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3 -Pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl 1,3-dimethyl-1-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1 -Butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-tri Methyl-2
-Propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1,3-butadiene group, 1,3- A pentadiene group, a 1,4-pentadiene group, a 1,4-hexadiene group, and the like are exemplified, but the invention is not limited to these.

  The present invention further provides a pharmaceutical composition comprising a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof, and one or more therapeutically active substances. . The above therapeutically active substances are TNF-α inhibitors, COX-1 / COX-2 inhibitors, COX-2 inhibitors, glucocorticoids, interleukin inactivating antibodies, chemokine receptor modulators, histamine H1 receptor antagonists / Antihistamine, leukotriene receptor antagonist, VLA-4 antagonist, corticosteroid, corticosteroid, β2-agonist, theophylline, leukotriene biosynthesis inhibitor, PDE4 inhibitor, opioid analgesic, anticoagulant, β -Selected from blockers, β-adrenergic receptor agonists, ACE inhibitors or HMG-CoA reductase inhibitors.

Claims (13)

A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

Where X ¹ , X ² , X ³ , X ⁴ are each independently N or C (R ¹ ) and X ⁵ is N or C (R ² );
R ¹ is hydrogen, cyano, nitro, hydroxy, carboxy, amino, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 Alkoxy, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _5-8 cycloalkenyl, C _2-6 alkynyl, C _1-6 alkylthio, C _1-6 alkylamino, di (C _{1 -6} alkyl) amino, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylsulfonyl, C _1-6 alkylaminosulfonyl, C _1-6 Alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl, di (C _1-6 alkyl) aminosulfonyl, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy;
R ² is hydrogen, cyano, nitro, hydroxy, carboxy, amino, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 Alkoxy, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl C _2-6 alkenyl, C _5-8 cycloalkenyl, C _5-8 cycloalkenyl C _1-6 alkyl , C _2-6 alkynyl, C _1-6 alkylthio, phenyl, phenyl C _1-6 alkyl, naphthyl, C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl C _1-6 alkyl, C _1-6 alkyl Amino, di (C _1-6 alkyl) amino, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylsulfonyl, C _1-6 alkylamino sulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) Karubamo Le, di (C _1-6 alkyl) aminosulfonyl, be a C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , and p is 1, 2, 3, 4, 5 or 6;

Is —C═, R ^1a and R ^1b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6. Alkoxy or C _3-8 cycloalkyl; wherein R ^1a and R ^1b are attached to them and C _3-8 cycloalkyl or at least one of the O, N or S atoms C _3-8 heterocycloalkyl may be formed; the above C _3-8 cycloalkyl and C _3-8 heterocycloalkyl are optionally 1, 2, 3, 4, 5, or 6 substituents The substituents here are independently selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy ;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or C _3-8 cycloalkyl; where R ^1a and R ^1b are ^1b may form a C _3-8 cycloalkyl or C _3-8 heterocycloalkyl containing at least one of the O, N or S atoms with the C atom bonded to them; _3-8 cycloalkyl and C _3-8 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;
W is R ^2a OC (O)-, (R ^2a ) ₂ NC (O)-, R ^2a C (O) NHC (O)-, tetrazolyl or R ^2a S (O) ₂ NHC (O)-;
R ^2a is hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, phenyl or tolyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1, 2, 3, 4, 5 or 6;

Is —C═, R ^3a and R ^3b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-8 cycloalkyl; R ^3a and R ^3b may form a C atom bonded to them and a C _3-8 cycloalkyl or C _3-8 heterocycloalkyl containing at least one of O, N or S atoms. . The above C _3-8 cycloalkyl and C _3-8 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently Selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy or C _3-8 cycloalkyl;

R ^3a and R ^3b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-8 cycloalkyl; wherein R ^3a and R ^3b are ^3b may form a C _3-8 cycloalkyl or C _3-8 heterocycloalkyl containing at least one of the O, N or S atoms with the C atom bonded to them; _3-8 cycloalkyl and C _3-8 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy or C _3-8 cycloalkyl;
X is an aryl group or a heterocyclic group, and X may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy, Selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy or C _3-8 cycloalkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-6 alkyl;
Y is C _3-8 cycloalkyl, an aryl group or a 3-10 membered heterocyclic group, Y may optionally be substituted with 1, 2, 3, 4, 5 or 6 substituents; Substituents are independently hydroxy, halogen, cyano, nitro, C _1-6 alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _{1- 6} alkyl, C _1-6 alkoxy C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _3-8 cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 Alkylthio, phenyl, phenoxy, C _5-8 heterocycloalkyl, C _5-8 heterocycloalkoxy, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _{1- 6} alkylsulfonyl, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 Cyl) carbamoyl, di (C _1-6 alkyl) aminosulfonyl, C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy. In the general formula (I), X ¹ , X ² , X ³ and X ⁴ are each independently N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen, cyano, hydroxy, amino, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _{3 -8} cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _5-8 cycloalkenyl, C _1-6 alkylthio, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 Alkylcarbamoyl, formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl, di (C _1-6 alkyl) aminosulfonyl C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyloxy;
R ² is hydrogen, cyano, amino, nitro, hydroxy, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl C _2-6 alkenyl, C _5-8 cycloalkenyl, C _5-8 cycloalkenyl C _1-6 alkyl, C _2-6 alkynyl, phenyl, phenyl C _1-6 alkyl, naphthyl, C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl C _1-6 alkyl, C _1-6 alkylamino, di (C _1-6 Alkyl) amino, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl or di ( C _1-6 alkyl) aminosulfonyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1, 2, 3, 4 or 5;

Is —C═, R ^1a and R ^1b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl. Where R ^1a and R ^1b are bound to the C atom and C _3-6 cycloalkyl or C _3-6 heterocycloalkyl containing at least one of O, N or S atoms The above C _3-6 cycloalkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; Are independently selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 alkoxy;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl; where R ^1a and R ^1b are ^1b may form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl containing at least one of O, N or S atoms with the C atom bonded to them; _3-6 cycloalkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C Selected from _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;
W is R ^2a OC (O)-, (R ^2a ) ₂ NC (O)-or tetrazole,
R ^2a is hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1, 2, 3, 4 or 5;

Is —C═, R ^3a and R ^3b are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl or C _3-6 cycloalkyl; where R ^3a and R ^3b are a C atom bonded to have, C _3-6 cycloalkyl or O, may also form a C _3-6 heterocycloalkyl containing at least one of N or S atoms; above C _3-6 cycloalkyl Alkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C _1-6 alkyl , Halogenated C _1-6 alkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;

R ^3a and R ^3b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or C _3-6 cycloalkyl; where R ^3a and R ^3b are ^3b may form a C _3-8 cycloalkyl or C _3-6 heterocycloalkyl containing at least one of O, N or S atoms with the C atom bonded to them; _3-6 cycloalkyl and C _3-6 heterocycloalkyl may be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents; these substituents are independently halogen, hydroxy , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl;
X is an aryl group or a heterocyclic group, and X may be optionally substituted with 1, 2, 3, 4 or 5 substituents; these substituents are independently halogen, hydroxy, C ₁ Selected from _-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-6 alkyl;
Y is C _3-8 cycloalkyl, an aryl group or a 3-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2, 3, 4 or 5 substituents; Is independently hydroxy, halogen, cyano, C _1-6 alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, halogen C _1-6 alkoxy, C _3-8 cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylthio, phenyl, phenoxy, C _5-8 heterocycloalkyl, C _5-8 heterocycloalkoxy, C _1-6 alkylcarbonyl, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di ( C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) selected from aminosulfonyl That,
2. The compound according to claim 1, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. In the general formula (I), X ¹ , X ² , X ³ and X ⁴ are each independently N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 Alkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkyl Sulfonylamino, di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl;
R ² is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 alkenyl, C _5-8 cycloalkenyl C _1-6 alkyl, phenyl, phenyl C _1-6 alkyl, naphthyl, C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl C _1-6 alkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino Di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1, 2, 3 or 4;

Is —C═, R ^1a and R ^1b are each independently hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl; where R ^1a And R ^1b may form a C _3-6 cycloalkyl with the C atom bound to them; the above C _3-6 cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents. The substituents here are independently selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 alkoxy;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl; where R ^1a and R ^1b are ^1b may form a C _3-6 cycloalkyl with the C atom attached to them; the above C _3-6 cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents The substituents here are independently selected from halogen, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;
W is R ^2a OC (O)-or (R ^2a ) ₂ NC (O)-
R ^2a is hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , and p is 1, 2, 3 or 4;

When is —C═, R ^3a and R ^3b are each independently hydrogen, halogen, C _1-6 alkyl or C _3-6 cycloalkyl;

When is —N—, R ^3a and R ^3b are each independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl;
X is a 6-10 membered aryl group or a 5-6 membered heterocyclic group, and X may be optionally substituted with 1, 2, 3 or 4 substituents; these substituents are independently Selected from halogen, hydroxy, C _1-6 alkyl or halogenated C _1-6 alkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-6 alkyl;
Y is C _3-8 cycloalkyl, a 6-10 membered aryl group or a 5-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2, 3 or 4 substituents; Substituents are cyano, hydroxy, halogen, C _1-6 alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _{3 -8} cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _1-6 alkylthio, C _5-8 heterocycloalkyl, C _5-8 heterocycloalkoxy, C _1-6 alkylcarbamoyl , Formamide group, C _1-6 alkylamido group, C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl The
3. The compound according to claim 2, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. In the general formula (I), X ¹ , X ² , X ³ and X ⁴ are each independently N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _1-6 alkylamino, di (C _1-6 alkyl) amino , C _1-6 alkylcarbamoyl, formamide group, C _1-6 alkylamide group, di (C _1-6 alkyl) carbamoyl or di (C _1-6 alkyl) aminosulfonyl;
R ² is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-6 Alkenyl, C _5-8 cycloalkenyl C _1-6 alkyl, phenyl, C _1-6 alkylamino or di (C _1-6 alkyl) amino;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1, 2 or 3;

When R is -C =, R ^1a and R ^1b are each independently hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl;

When R is —N—, R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or C _3-6 cycloalkyl;
W is R ^2a OC (O) —, R ^2a is hydrogen or C _1-4 alkyl;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1, 2 or 3;

When is —C═, R ^3a and R ^3b are each independently hydrogen, halogen or C _1-4 alkyl;

When is —N—, R ^3a and R ^3b are each independently hydrogen or C _1-4 alkyl;
X is a 6-10 membered aryl group or a 5-6 membered heterocyclic group, and X may be optionally substituted with 1, 2 or 3 substituents; these substituents are independently halogen, Selected from C _1-4 alkyl or halogenated C _1-4 alkyl;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-4 alkyl;
Y is a 6-10 membered aryl group or a 5-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2 or 3 substituents; the substituents here are halogen, cyano, C _{1 -6} alkyl, hydroxy C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkylamino or Selected from di (C _1-6 alkyl) amino,
4. The compound according to claim 3, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. In the general formula (I), X ¹ , X ² , X ³ and X ⁴ are each independently N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, formamide group, C _1-4 alkylamide group or C _3-6 cyclo Is alkyl;
R ² is hydrogen, halogen, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or phenyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1 or 2,

When is —C═, R ^1a and R ^1b are each independently hydrogen, halogen or C _1-4 alkyl;

When is —N—, R ^1a and R ^1b are each independently hydrogen or C _1-4 alkyl;
W is -C (O) OH;
L ^{2 is-} (C (R ^3a R ^3b )) _p- , p is 1 or 2,
R ^3a and R ^3b are each independently hydrogen or C _1-4 alkyl;
X is phenyl, pyridyl or pyrazinyl, X may optionally be substituted with 1 or 2 substituents; these substituents are independently halogen, C _1-4 alkyl or halogenated C _1- Selected from ₄ alkyls;
L ³ is —N (R ^5a ) —C (O) —, R ^5a is hydrogen or C _1-4 alkyl;
Y is a 6-10 membered aryl group or a 5-10 membered heterocyclic group, and Y may be optionally substituted with 1, 2 or 3 substituents; the substituents are independently halogen, Selected from cyano, C _1-4 alkyl or halogenated C _1-4 alkyl,
5. The compound according to claim 4, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. In the general formula (I), X ¹ , X ² , X ³ and X ⁴ are each independently N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, methylamino, formamide group, acetylamino or C _3-6 cycloalkyl;
R ² is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or phenyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ^{1 is-} (C (R ^1a R ^1b )) _p- , p is 1 or 2, and R ^1a and R ^1b are each independently hydrogen;
W is -C (O) OH;
L ² is —CH ₂ —;
X is phenyl, pyridyl or pyrazinyl, X may be substituted by 1 or 2 substituents; these substituents are independently selected from fluorine, chlorine, methyl, ethyl, isopropyl or trifluoromethyl That;
L ³ is —N (R ^5a ) —C (O) — and R ^5a is hydrogen or methyl;
Y is phenyl, pyridyl, pyrazolyl, naphthyl or 2,3-dihydrobenzo [b] [1,4] dioxanyl, Y may optionally be substituted with 1, 2 or 3 substituents; The substituents are independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl,
6. The compound according to claim 5, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. In the general formula (I), X ¹ , X ² , X ³ and X ⁴ are each independently N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen, fluorine, chlorine or C _1-4 alkyl;
R ² is hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ¹ is —CH ₂ —;
W is -C (O) OH;
L ² is —CH ₂ —;
X is phenyl, pyridyl or pyrazinyl, and X may optionally be substituted with 1 or 2 substituents; each substituent is independently fluorine, chlorine, methyl, ethyl or trifluoromethyl Chosen from;
L ³ is —N (R ^5a ) —C (O) — and R ^5a is hydrogen or methyl;
Y is phenyl, pyridyl, pyrazolyl, naphthyl or 2,3-dihydrobenzo [b] [1,4] dioxanyl, Y may optionally be substituted with 1, 2 or 3 substituents; The substituents are each independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl,
7. The compound according to claim 6, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. In the general formula (I), X ¹ , X ² and X ³ are each independently C (R ¹ ), X ⁴ is N or C (R ¹ ), and X ⁵ is N or C (R ² );
R ¹ is hydrogen or fluorine;
R ² is hydrogen or C _1-4 alkyl;

Are each independently -N- or -C =, and

Are not -N- at the same time;
L ¹ is —CH ₂ —;
W is -C (O) OH;
L ² is —CH ₂ —;
X is phenyl, pyridyl or pyrazinyl;
L ³ is —N (R ^5a ) —C (O) — and R ^5a is hydrogen or methyl;
Y is phenyl, pyridyl, pyrazolyl, naphthyl or 2,3-dihydrobenzo [b] [1,4] dioxanyl, Y may optionally be substituted with 1 or 2 substituents; Are each independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl or trifluoromethyl,
8. The compound according to claim 7, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. The compound according to any one of claims 1 to 8, selected from the following compound group, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

  A drug formulation comprising the compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt thereof and a stereoisomer thereof, and one or more drug carriers.   11. The drug preparation according to claim 10, which is an oral preparation, injection preparation, inhalation preparation, nasal preparation, transdermal absorption preparation, rectal administration preparation, ointment or gel preparation.   Asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronic rubella, basophilic leukocytosis, psoriasis, eczema, inflammatory bowel disease, ulcerative Any one of claims 1 to 9 for the preparation of a medicament for the treatment and / or prevention of diseases related to CRTH2 activity, selected from the group consisting of colitis, Crohn's disease, arthritis or chronic obstructive pulmonary disease Use of the compound described in the item, a pharmaceutically acceptable salt thereof and a stereoisomer thereof. A compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt thereof and a stereoisomer thereof;
TNF-α inhibitor, COX-1 / COX-2 inhibitor, COX-2 inhibitor, glucocorticoid, interleukin inactivating antibody, chemokine receptor modulator, histamine H1 receptor antagonist / antihistamine, leukotriene D4 receptor Antagonist, leukotriene antagonist, LTD4 antagonist, VLA-4 antagonist, corticosteroid, corticosteroid, β2-agonist, theophylline, leukotriene biosynthesis inhibitor, cyclooxygenase-2 inhibitor, phosphodiesterase type IV inhibitor, opioid analgesia One or more therapeutically active substances selected from the group consisting of drugs, anticoagulants, β-blockers, β-adrenergic agonists, angiotensin converting enzyme inhibitors or HMG-CoA reductase inhibitors;
A drug composition comprising: